WO2009092276A1 - Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof - Google Patents
Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof Download PDFInfo
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- WO2009092276A1 WO2009092276A1 PCT/CN2009/000001 CN2009000001W WO2009092276A1 WO 2009092276 A1 WO2009092276 A1 WO 2009092276A1 CN 2009000001 W CN2009000001 W CN 2009000001W WO 2009092276 A1 WO2009092276 A1 WO 2009092276A1
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel bicyclic substituted pyrazolone azo derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly thrombopoietin (TPC simulation) And their use as thrombopoietin receptor agonists.
- TPO Thrombopoietin
- the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL).
- TPO receptor also known as MPL.
- the TPO receptor has been successfully cloned and sequenced for amino acid sequence (Vigon et al., Proc. Nat. Acad. ScL 89: 5640-5644 (1992))
- TPO is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 1 1104-1 1 108 (1994); Barley et al., Cell 77: 1117-1 124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571- 574 (1994); and Sauvage et al., Nature 369: 533-538 (1994)). TPO is produced in the liver but mainly acts on the bone marrow, stimulating stem cell differentiation.
- TPO is a major regulator of thrombocytopenia and a large number of studies on increasing platelet count, size, and increasing the involvement of experimental animal isotope in platelets (Metcalf Nature 369:519-520 (1994)).
- TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects.
- TPO can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplantation for the treatment of cancer and lymphoma.
- the thrombopoietin analog dtrombopag is reported by GSK in the patent (WO-00189457/WO-01089457/WO-2006064957) and exhibits considerable activity.
- the present invention discloses a series of compounds that are more effective as TPO receptor agonists and are potent TPO mimetics. Summary of the invention
- A is selected from a carbon atom or an oxygen atom
- R is selected from a hydrogen atom or an alkyl group
- R, . R 2 and each independently selected from a hydrogen atom, a fluorenyl group, an alkoxy group, a halogen, an 'aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is optionally further selected from one or more selected from one or more Substituted with a substituent of a mercapto group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester;
- R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
- R is selected from a hydrogen atom or a sulfhydryl group
- aryl or heteroaryl group wherein the aryl or heteroaryl group is optionally further selected from one or more selected from the group consisting of fluorenyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid ester Substituted by a substituent;
- R 2 , R 3 and R 4 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group or a halogen;
- R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
- R s , R 9 , . And R n are each independently selected from a hydrogen atom or an alkyl group
- n 0, 1 or 2.
- Preferred compounds of the compounds of the formula (I) of the present invention include, but are not limited to:
- the present invention includes a compound represented by the formula (IA) which is an intermediate for the synthesis of the compound of the formula (I):
- A is selected from a carbon atom or an oxygen atom
- R s , R 9 , R IG and R n are each independently selected from a hydrogen atom or a fluorenyl group
- n 0, 1 or 2.
- Preferred compounds of the compound of the formula (IA) of the present invention include, but are not limited to:
- the amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetoacetate in a suitable solvent ( Condensation under heating, such as acetic acid, ethanol, etc., gives the compound of formula (IA).
- another aspect of the present invention provides a process for the preparation of the compound (I) of the formula, which comprises:
- a substituted aniline compound By diazotizing a substituted aniline compound with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then reacting a compound of the formula (IA) with an alkaline solution (such as sodium hydrogencarbonate, carbonic acid) A coupling reaction occurs in potassium hydrogen) to give a compound of the formula ⁇ .
- a suitable acidic solution such as nitric acid, sulfuric acid, hydrochloric acid
- an alkaline solution such as sodium hydrogencarbonate, carbonic acid
- the present invention relates to the use of a compound of the formula and ( ⁇ ) in the manufacture of a medicament for the treatment of thrombocytopenia.
- a therapeutically effective amount of a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, soluble receptor, receptor agonist or antagonist
- a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, soluble receptor, receptor agonist or antagonist
- An antibody or a peptide or small molecule that functions in the same mechanism as one or more of the drugs.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula ⁇ and ( ⁇ ), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable salt.
- the composition may further comprise a therapeutically effective amount of a drug selected from the group consisting of: a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist.
- a drug selected from the group consisting of: a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist.
- the combined use includes the simultaneous use or sequential use of the compounds described herein.
- the present invention relates to a method of preparing a pharmaceutical composition
- a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula ⁇ and ( ⁇ ) and a pharmaceutically acceptable salt, hydrate or solvate thereof, the method comprising
- the compounds of formula (I) and ( ⁇ ) are combined with a pharmaceutically acceptable carrier and diluent.
- Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms.
- An alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group or the like is preferable.
- lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
- the fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an indenyl group, a decyloxy group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an aryl group. , heteroaryl, carboxylic acid or carboxylic acid ester.
- Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, Carbocyclic aryl, heteroaryl and biaryl.
- the block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. , heteroaryl, carboxylic acid or carboxylic acid ester.
- Heteroaryl means an aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and hetero atoms including oxygen, sulfur and nitrogen.
- the ring may be a 5- or 6-membered ring.
- the heteroaryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-fluorenylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group and the like.
- the heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl.
- Base heteroaryl, carboxylic acid or carboxylic acid ester.
- Haldroxy means an -OH group.
- Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- the methoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an indenyl group, a decyloxy group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an aromatic group.
- Base heteroaryl, carboxylic acid or carboxylic acid ester.
- Halogen means fluoro, chloro, bromo or iodo.
- Amino means -NH 2 .
- Neitro means -N0 2 .
- Alkoxy means -0-(alkyl).
- the amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetoacetate in a suitable solvent (such as acetic acid, Ethanol or the like is condensed under heating to give a compound of the formula (IA).
- the substituted o-bromophenol is nitrated by sodium nitrate to obtain a nitrophenol.
- the nitrophenol is alkylated with a halogenated sulfhydryl group such as methyl iodide at a suitable temperature to obtain a hydroxy-protected nitrophenol; a hydroxy-protected nitrate
- a halogenated sulfhydryl group such as methyl iodide
- R substituted aryl compound
- R substituted aryl compound under hydrogen atmosphere, palladium/carbon reduction to obtain aryl aniline, aryl aniline in bromine to remove sulfhydryl groups to obtain deprotected aniline.
- the substituted aryl compound is deprotected from the sulfhydryl group in hydrogen bromide to give the deprotected nitro compound.
- the nitro compound is reduced under palladium on carbon under hydrogen to give the deprotected aryl aniline.
- the HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150> ⁇ 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
- the pressurized hydrogenation reaction uses a Pau 3916EKX hydrogenation apparatus and a clear blue QL type hydrogen generator;
- the microwave reaction uses a CEM Discover-S 908860 microwave reactor;
- the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
- the solution in the reaction means an aqueous solution
- 5-Aminoindan lg (3.59 g, 27.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min.
- 10 mL of sodium nitrite solution (1.86 g, 27.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.
- the stannous chloride dihydrate (24.4 g, 108.0 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice salt bath, and the intermediate solution was added thereto, and the mixture was allowed to react to room temperature for 1.5 hours. The mixture was adjusted to pH 9 with 40% EtOAc EtOAc (EtOAc)EtOAc. Yield: 51.3%.
- 2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid solution (50%) in an ice salt bath, and sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid solution was added dropwise. (25%), reacted at room temperature for 1.5 hours. TLC was traced to the disappearance of the starting material, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2).
- 3-carboxylic acid 3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (296 mg, 1.20 mmol) was dissolved in 10 mL of hydrochloric acid (IN) under ice bath, and 10 mL of sodium nitrite solution was added dropwise. (91 mg, 1.32 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (257 mg, 1.20 mmol) with sat. sodium bicarbonate The solution was adjusted to pH 8 and added to 10 mL of ethanol and allowed to warm to room temperature overnight.
- 2-Amino-5,6,7,8-tetrahydronaphthalene 3g (3.68 g, 25.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min.
- 10 mL of sodium nitrite solution (1.72 g, 25.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.
- Ethyl 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylate 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl 4-methylbenzenesulfonate (2.73) was added. g, 14.69 mmol) and sodium tert-butoxide (2.02 g, 20.99 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was filtered, and the filter cake was washed with THF. The product 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, m.p.).
- 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide salt 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 9b ( 2.79 g, 11.97 mmol) was dissolved in 25 mL of dichloromethane, and boron tribromide (23.9 mL, 2.0 mol/L) was added dropwise and allowed to react at room temperature for 1 hour. TLC was traced to the disappearance of the starting material, 5 mL of methanol was added, and concentrated under reduced pressure.
- the TLC was traced to the disappearance of the starting material, cooled to room temperature, and concentrated under reduced pressure to remove acetic acid.
- the acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined with saturated sodium chloride solution.
- the organic layer was dried (MgSO4jjjjjjjjjjjj 5-yl)-2,4-dihydropyrazole-3-one 19d (130 mg, light yellow oily liquid). Yield: 13.6%.
- 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene 2-carboxylic acid 24b (0.29 g, 1 mmol) dissolved in To 30 mL of ethyl acetate, 0.06 g of palladium-carbon and cesium formate (0.25 g, 4 mmol) were added, and the mixture was heated and refluxed for 45 minutes. The TLC was traced to the disappearance of the starting material, and the palladium-carbon was removed by filtration.
- 3-Amino-3'-(1 ⁇ -tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (188 mg, 0.74 mmol) was dissolved in 4 mL of 2N hydrochloric acid and added dropwise. 1 mL of sodium nitrite solution (57 mg, 0.82 mmol), react for 30 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (159 mg , 0.74 mmol), the pH was adjusted to 8 with saturated sodium bicarbonate, and 0.5 mL of ethanol was added and allowed to react overnight at room temperature.
- 2-(2'-Hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32d (334 mg, 1.11 mmol) was dissolved in hydrochloric acid (3.7 mL). In 1 mol/L), 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) was added dropwise, and the reaction was carried out for 20 minutes, followed by the addition of 2-indan-5-yl-5-methyl-2,4-dihydropyridinium. Zylin-3-one li (214 mg, 1 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 5 mL of ethanol was added and allowed to react overnight at room temperature.
- 3-(4-Bromophenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) was added to a 250 mL single-necked flask and dried in vacuo for 20 min.
- Thionyl chloride (20 mL, 276 mmol) was added with stirring and heated to reflux overnight. Most of the solvent was removed under reduced pressure, and 100 mL of dichloromethane was added, and aluminum chloride (24.5 g, 25.8 mmol) was added portionwise with stirring, and a large amount of gas was released, and the reaction was refluxed overnight.
- the reaction mixture was poured into 200 g of crushed ice, and a large amount of solid was precipitated, which was purified by silica gel chromatography. 6-Bromo-indanone 38b (18.34 g, yellow solid). Yield: 96.6%.
- methyl group phenylphosphonium bromide (4.56 g, 12.76 mmol) was dissolved in 25 mL of tetrahydrofuran, and potassium t-butoxide (1.5 g, 13.4 mmol) was added in one portion, and the mixture was stirred at room temperature for 35 minutes.
- 6-Bromo-indan-1 -one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran, and the solution was added dropwise with stirring. The resulting solution was stirred at room temperature for 1 hour and quenched with 25 mL of water. reaction. The mixture was extracted with chloroform (25 mL EtOAc). EtOAc (EtOAc m. Separation and purification gave the title product 6-bromo-1-methylene-indane 38c (830 mg,yield of yellow oil). Yield: 93.4%. MS nVz (ESl): 208 [M-1] third
- 6-Bromomethylene indan 38c (4.91 g, 23.5 mmol) was dissolved in ethyl acetate, palladium-carbon (0.98 g) was added, and the reaction was carried out for 4 hours at room temperature under a hydrogen atmosphere, and the TLC was traced until the starting material disappeared. The filtrate was filtered, and the filtrate was evaporated tolulululululululululululululululululululululululululululululu
- n-butyllithium (8.6 mL, 13.76 mmol) was added to a three-necked flask, and added to 8 mL of tetrahydrofuran under a dry ice-acetone bath, and 6-bromo-1-methylindane 38d was added with stirring. 1.32 g, 6.26 mmol), the obtained solution was reacted in a dry ice-acetone bath for 2 hours, and a solution of di-tert-butyl azodicarboxylate G.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran was added dropwise, stirring was continued for 30 minutes, and ice was removed.
- Ethyltriphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran, and potassium t-butoxide (5.29 g, 47.3 mmol) was added and stirred at room temperature for 1 hour.
- 6-Bromo-indan-1-one 38b (3.39 g, 18.6 mmol) was dissolved in 25 mL of tetrahydrofuran, and the solution was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched by the addition of 150 mL of water. The reaction mixture was extracted with dichloromethane (50 mL ⁇ 4). The organic phase was combined and washed with brine (45 mL ⁇ 2) The organic layer was dried over sodium sulfate, filtered and evaporated, evaporated, evaporated, evaporated, evaporated.
- 6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate at room temperature, and palladium-carbon (0.61 g) was added in a hydrogenation apparatus at 3 atm. After hydrogenation with hydrogen, the mixture was reacted for 5 hours at room temperature, and the reaction of the material was monitored by TLC.
- the di-tert-butyl azodicarboxylate was dissolved in 15 mL of tetrahydrofuran, added dropwise to the above reaction solution, and the mixture was further stirred in a dry ice-acetone bath for 0.5 hour, and the dry ice-acetone bath was removed, and the reaction solution was naturally warmed to room temperature. After stirring for 18 hours, the reaction of the starting material was completely monitored by TLC. To the reaction mixture was added 25 mL of a saturated solution of ammonium chloride to quench the reaction.
- 5-P-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c 333 mg, 1.1 mmol was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) under ice bath. Add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) for 20 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydro Pyrazol-3-one 8i (242 mg, 1.0 mmol) was added portionwise sodium bicarbonate (1.4 g, 16.67 mmol) and 3 mL of EtOAc.
- 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L). Add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) dropwise for 20 minutes, then add 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazole 3-ketone 38c (228 mg, 1.0 mmol), sodium bicarbonate (1.4 g, 16.67 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature.
- 6-Bromo-indan-1-one 38b (6.02 g, 28.5 mmol) and iodoguanidine (4.4 mL, 70 mmol) were dissolved in 200 mL of THF (dry) and stirred at room temperature for 15 min. g, 68.2 mmol), stirring for 2 hours, TLC was monitored until the reaction of the starting material was completed, 150 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL ⁇ 2), and the organic phase was washed with saturated brine. The mixture was dried over sodium sulfate, filtered and evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
- the mixture is adjusted to ppHi to basic with saturated sodium carbonate, extracted with ethyl acetate (50 mL ⁇ 3), combined organic phase, organic Wash with saturated saline, no The aqueous solution was dried over sodium sulfate, and filtered, and then filtered, evaporated, evaporated, evaporated, evaporated.
- 5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 5-(2-methoxy-3-nitrophenyl)-2-methylfuran 3-carboxylic acid 53c (450 mg, 1.62 mmol) was dissolved in methanol, 45 mg of palladium/carbon was added, and the mixture was stirred under reflux for 4 hours under a hydrogen atmosphere, and the residue was evaporated to the residue, and the filtrate was filtered.
- the product 5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 53d (370 mg, white solid).
- reaction solution was sequentially saturated sodium carbonate solution and sodium thiosulfate solution ( 2M) Washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the filtrate was concentrated under reduced pressure to give the title product 2,2,2-trichloro-1 -(4-iodo-1 H -pyrrol-2-yl)-acetyl 57c (47 g, yellow solid), Yield: 92%.
- Methyl 4-iodo-1-(toluene-4-sulfonyl)- 1 H-pyrrole-2-carboxylate Methyl 4-iodo-1H-pyrrole-2-carboxylate 57d (25.1 g, 100 mmol)
- triethylamine 30.6 mL, 220 mmol
- 4-dimethylaminopyridine (1.22 g, 10 mmol)
- p-toluenesulfonic acid 21 g, 110 mmol
- reaction mixture was extracted with methylene chloride (50 mL ⁇ 3).
- organic phase was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, white solid), yield: 80.2%.
- mouse IL-3 (chemicon Catalog no.IL015 )
- Plasmid construction Purchasing the EX-B0010-M02 plasmid (FulenGen) using the QuikChange® Multi Site Directed Mutagenesis Kit (Stratagene) kit according to the TPOR gene sequence provided by Entrez Gene ID: 4325, Refseq: NM-005373 2 point mutation.
- the multi-point mutation primer sequences are: g491a: 5'-gggaacttcagatcagctgggaggagccg-3 ' , g491a- antisense:
- BAF3-TPOR cell line A BaF3 cell line stably expressing a highly functional TPO receptor was constructed. The by expressing human after the 2-point mutant TPO receptor and screening gene neomycin the EX-B0010-M02 plasmid; 25 ⁇ ⁇ transfected with wild-type BaF3 cells (1X10 7), transfection instruments as Electro Square Porator ECM830 (BTX Division of Genetronic, Inc. US), transfection conditions: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening.
- BAF3-TPOR was cultured in RPMI 1640 (Gibco, US) medium, 10% FB (Gibco, US) S, 800 ng/ml G418, 5 ng/mU rmIL-3 (Chemicon, US).
- Centrifuge the cells by centrifugation Take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 ml of cell culture medium containing no IL3, centrifuge at lOOOOrpm for 5 minutes, discard the supernatant;
- test compound powder was formulated into 10 mM stock solution in DMSO, and diluted to different concentrations with RPM11640: 30 ⁇ , 10 ⁇ , 3 ⁇ , ⁇ , 0.3 ⁇ , 0 ⁇ 1 ⁇ , 0.03 ⁇ , 0 ⁇ 01 ⁇ , 0.003 ⁇ ,
- Rats were used as test animals, and the concentration of the drug in plasma was measured by LC/MS/MS method at different times after administration of Example 1, Example 15 and Example 29 by intragastric administration.
- the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- Example 1 Example 15 and Example 29
- the pharmacokinetic parameters of the compounds of the invention are as follows:
- test results showed that each of the compounds was well absorbed after the rats were intragastrically administered with the above compounds of the present invention.
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Abstract
The bicycle-substituted pyrazolon-azo derivatives of formula (I) or pharmaceutical acceptable salts, hydrates or solvates thereof, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as thrombopoietin (TPO) mimetics and their use as agonists of thrombopoietin receptor. The definitions of substituents of formula (I) are the same as the description.
Description
双环取代吡唑酮偶氮类衍生物、 其制备方法及其在医药上的应用 Bicyclic substituted pyrazolone azo derivative, preparation method thereof and application thereof in medicine
技术领域 Technical field
本发明涉及通式 (I)所示新的双环取代吡唑酮偶氮类衍生物、其制备方法以及含 有该衍生物的药物组合物、 .以及其作为治疗剂特别是血小板生成素 (TPC模拟物和 它们用作血小板生成素受体激动剂的用途。 The present invention relates to a novel bicyclic substituted pyrazolone azo derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly thrombopoietin (TPC simulation) And their use as thrombopoietin receptor agonists.
背景技术 Background technique
血小板生成素（Thrombopoietin， TPO), 又称为巨核细胞生长发育因子 Thrombopoietin (TPO), also known as megakaryocyte growth factor
(megakaryocyte growth and development factor, MGDF)， 血小板生成朿 lj激因子 (thrombocytopoiesis stimulating factor, TSF)， c-Mpl 酉己体 (c-myeloproliferative leukemia ligand, c-Mpl), mpl 配体， megapoietin是一种与产生血小板有关的糖蛋白 (Wendling. R, et. al., Biotherapy 10(4):269-77 (1998); Kuter D.l. et al., The Oncologist; 1 :98-106(1996); Metcalf, Nature 369: 519-520 (1994))。 (megakaryocyte growth and development factor, MGDF), thrombocytopoiesis stimulating factor (TSF), c-myeloproliferative leukemia ligand (c-Mpl), mpl ligand, megapoietin Glycoprotein associated with platelet production (Wendling. R, et. al., Biotherapy 10(4): 269-77 (1998); Kuter Dl et al., The Oncologist; 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994)).
在某些情况下， TPO的活性源自 TPO与 TPO受体 (也称 MPL)的结合。 TPO受体已 经被成功克隆， 也进行了氨基酸序列的测序 (Vigon et al., Proc. Nat. Acad. ScL 89:5640-5644(1992)) In some cases, the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL). The TPO receptor has been successfully cloned and sequenced for amino acid sequence (Vigon et al., Proc. Nat. Acad. ScL 89: 5640-5644 (1992))
TPO是一种 332-氨基酸糖基化多肽，在调节巨核细胞生成和由骨髓巨核细胞产 生血小板的过程中起着关键的作用（Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 1 1104-1 1 108 (1994); Barley et al., Cell 77: 1117-1 124 (1994); Kaushansky et al., Nature 369:568-571 ( 1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994))。 TPO产生于肝脏但主要作用于骨髓， 刺激干细胞分化. 成为巨核细胞以及巨核细胞的增殖， 多倍体化， 最重要的是进入血小板身体循环 分裂。 TPO在血小板减少症和大量关于增加血小板数量、大小、增加实验动物同位 素参入血小板的研究中是一种主要的调节剂 (Metcalf Nature 369:519-520 (1994))。 TPO被认为主要通过几个途径影响巨核细胞生成： （1)引起巨核细胞大小和数量的 增加； （2)增加 DNA内含物， 多倍体的形式， 巨核细胞； （3)增加巨核细胞的核内有 丝分裂； （4)增加成熟的巨核细胞； （5)增加前体细胞的百分比， 小乙酰胆碱酶一阳 性形式的细胞， 骨髓细胞。 ■ TPO is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 1 1104-1 1 108 (1994); Barley et al., Cell 77: 1117-1 124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571- 574 (1994); and Sauvage et al., Nature 369: 533-538 (1994)). TPO is produced in the liver but mainly acts on the bone marrow, stimulating stem cell differentiation. It becomes the proliferation of megakaryocytes and megakaryocytes, polyploidization, and most importantly, it enters the platelet body and divides. TPO is a major regulator of thrombocytopenia and a large number of studies on increasing platelet count, size, and increasing the involvement of experimental animal isotope in platelets (Metcalf Nature 369:519-520 (1994)). TPO is thought to affect megakaryocyte production mainly through several pathways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing megakaryocytes Nuclear mitosis; (4) increase of mature megakaryocytes; (5) increase the percentage of precursor cells, small acetylcholine-positive form of cells, bone marrow cells. ■
血小板是血液凝固必需的， 当它的数量非常低时， 病人就有出血死亡的危险。 因此， TPO己经被用于诊断和治疗多种血液疾病，如主要由血小板缺陷引起的疾病。 同时， TPO可以用于治疗血小板减少症，尤其是为治疗癌症和淋巴瘤而进行的化疗、 放疗和骨髓移植。 Platelets are essential for blood clotting, and when it is very low, the patient is at risk of bleeding. Therefore, TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects. At the same time, TPO can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplantation for the treatment of cancer and lymphoma.
患者因血小板减少症而导致血小板水平恢复过慢是一个严重的问题， 因此希 望可以找到一种治疗血小板减少症的活性 TPO类似物。几年前， 多肽类 TPO类似物
的发展被报导。 （WO96/40750, W098/25965) 这些多肽可以结合并活化 TPO受体， 但是不具备天然 TPO的序列同源性。最近几年， 一些小分子的活性 TPO类似物被报 导。 包括 1,4-苯并二氮杂卓 -2-酮类 (JP11001477), 由希夫碱配体得到的金属络合物 (WO 99/11262), 环多胺衍生物 (WO00/28987), 噻唑 -2-¾-苯酰胺类 (WO01/07423, WO01/53267) , 偶氮 -芳基衍生物（WO00/35446, WO 1/17349), 2-芳基-萘唑类 (WOOl/39773, WO01/53267)和缩氨基脲衍生物 (WO01/34585)。 在基于细胞的体系 内，所有这些分子都能活化细胞膜上的 TPO受体的信号转导途径，一些类型能直接 作用于 TPO受体本身。 据介绍， 取代缩氨硫脲居然是非常有效的 TPO受体激动剂。 这一系列中一些最优先的化合物被发现可以刺激 TPO-responsive人类细胞系和低 于 ΙΟΟηΜ的人类骨髓培养液中的 TP0的增殖和分化。 Patients with thrombocytopenia due to thrombocytopenia are a serious problem, so it is hoped that an active TPO analog for thrombocytopenia can be found. A few years ago, peptide TPO analogs The development was reported. (WO 96/40750, W098/25965) These polypeptides bind to and activate the TPO receptor, but do not possess the sequence homology of native TPO. In recent years, some small molecule active TPO analogs have been reported. Including 1,4-benzodiazepine-2-ones (JP11001477), metal complexes obtained from Schiff base ligands (WO 99/11262), cyclic polyamine derivatives (WO 00/28987), thiazole -2-3⁄4-benzamides (WO 01/07423, WO 01/53267), azo-aryl derivatives (WO 00/35446, WO 1/17349), 2-aryl-naphthazoles (WOOl/39773, WO01 /53267) and a semicarbazone derivative (WO 01/34585). Within a cell-based system, all of these molecules activate the signal transduction pathway of the TPO receptor on the cell membrane, and some types act directly on the TPO receptor itself. According to reports, the replacement of thiourea is actually a very effective TPO receptor agonist. Some of the most preferential compounds in this series have been found to stimulate the proliferation and differentiation of TPO-responsive human cell lines and TP0 in human bone marrow broth below ΙΟΟηΜ.
GSK公司在专利 ( WO-00189457/ WO-01089457/WO-2006064957)中报道血小板 生成素类似物 dtrombopag, 并表现出了相当的活性。 The thrombopoietin analog dtrombopag is reported by GSK in the patent (WO-00189457/WO-01089457/WO-2006064957) and exhibits considerable activity.
本发明公开了一系列化合物且更有效地用作 TPO受体激动剂， 是有效的 TPO 模拟物。 发明内容 The present invention discloses a series of compounds that are more effective as TPO receptor agonists and are potent TPO mimetics. Summary of the invention
为了克服现有技术的不足之处， 本发明的目的在于提供一种通式 (I)所示的双环 取代吡唑酮偶氮类衍生物， 以及它们的互变异构体、 对映体、 非对映体、 消旋体 和药学上可接受的盐、 水合物或溶剂化合物， 以及代谢产物和代谢前体或前药。 In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a bicyclic substituted pyrazolone azo derivative represented by the general formula (I), and tautomers, enantiomers thereof, Diastereomers, racemates and pharmaceutically acceptable salts, hydrates or solvent compounds, as well as metabolites and metabolic precursors or prodrugs.
A选自碳原子或氧原子； A is selected from a carbon atom or an oxygen atom;
R选自氢原子或烷基； R is selected from a hydrogen atom or an alkyl group;
R, . R2、 和 各自独立地选自氢原子、 垸基、 烷氧基、 卤素、 '芳基或杂芳 基， 其中芳基或杂芳基任选进一歩被一个或多个选自垸基、 卤素、 羟基、 四唑基、 咪唑、 二氢咪唑、 羧酸或羧酸酯的取代基所取代； R, . R 2 , and each independently selected from a hydrogen atom, a fluorenyl group, an alkoxy group, a halogen, an 'aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is optionally further selected from one or more selected from one or more Substituted with a substituent of a mercapto group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester;
R5、 和 R7各自独立地选自氢原子、 垸基、 烷氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
R8、 R9、 RI Q和 各自独立地选自氢原子或垸基； 且
n是 0， 1或 2。 R 8 , R 9 , R IQ and each independently selected from a hydrogen atom or a fluorenyl group; n is 0, 1 or 2.
本发明优选的实施方案中， In a preferred embodiment of the invention,
A选自碳原子或氧原子； A is selected from a carbon atom or an oxygen atom;
R选自氢原子或垸基； R is selected from a hydrogen atom or a sulfhydryl group;
选自芳基或杂芳基， 其中芳基或杂芳基任选进一歩被一个或多个选自垸基、 卤素、 羟基、 四唑基、 咪唑、 二氢咪唑、 羧酸或羧酸酯的取代基所取代； R2、 R3 和 R4各自独立地选自氢原子、 垸基、 烷氧基或卤素； Or an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further selected from one or more selected from the group consisting of fluorenyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid ester Substituted by a substituent; R 2 , R 3 and R 4 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group or a halogen;
R5、 和 R7各自独立地选自氢原子、 垸基、 烷氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
Rs、 R9、 。和 Rn各自独立地选自氢原子或烷基； 且 R s , R 9 , . And R n are each independently selected from a hydrogen atom or an alkyl group;
n是 0， 1或 2。 本发明通式 （I ) 所示的化合物的优选化合物包括， 但不限于: n is 0, 1 or 2. Preferred compounds of the compounds of the formula (I) of the present invention include, but are not limited to:
18 基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼 基] -苯基 } -噻吩 -2-羧酸18-yl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenyl}-thiophene-2-carboxylic acid
2'-羟基 -3'-{N'-[3-甲基 -5-氧代 -1-(1 , 1 ,3,3-四甲基茚满 -5-基) -1 ,5-二2'-hydroxy-3'-{N'-[3-methyl-5-oxo-1-(1,1,3,3-tetramethylindan-5-yl)-1,5-di
】9 】9
氢吡唑—4-亚基]-肼基 联苯基 -3-羧 酸 Hydropyrazol-4-ylidene]-indenylbiphenyl-3-carboxylic acid
2'-羟基 -5'-甲基 -3'-{N'-[3-甲基 -5-氧 v//工 2'-hydroxy -5'-methyl -3'-{N'-[3-methyl -5-oxygen v//
代 -1-(U ,3,3-四甲基茚满 -5-基) -1,5- 0 -1-(U,3,3-tetramethylindan-5-yl)-1,5- 0
二氢吡唑 -4-亚基] -肼基 }-联苯基 - 3- Dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-
3'-[N'-( 1 -双环 [4.2.0]辛垸- 1 ,3,5-三烯 o 〇I - -3-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 1 3'-[N'-(1-bicyclo[4.2.0]octyl-1,3,5-triene o 〇I--3-yl-3-methyl-5-oxo-1,5- Dihydropyrazole 1
-4-亚基) -肼基 ]-2'-羟基 -5'-甲基联苯 o -4-subunit)-mercapto]-2'-hydroxy-5'-methylbiphenyl o
基 -3-羧酸 Carboxy-3-carboxylic acid
5-{3-[Ν'- (卜双环 [4.2.0]辛烷 -1 ,3,5-三 烯—3—基—3—甲基—5—氧代— 二氢吡 2 5-{3-[Ν'- (Bu bicyclo[4.2.0]octane-1,3,5-triene-3-yl-3-methyl- 5 -oxo-dihydropyridin 2
唑 -4-亚基) -肼基 ]-2-羟基苯基} -呋喃 。 Azole-4-ylidene)-indenyl]-2-hydroxyphenyl}-furan.
2-双环 [4.2.0] 辛垸 -1 ,3,5-三烯 -3-基 -4-{[2-羟基 -3'-(1 Η-四唑 -5-基) -联苯 3 2-bicyclo[4.2.0] octane-1,3,5-trien-3-yl-4-{[2-hydroxy-3'-(1 Η-tetrazol-5-yl)-biphenyl 3
-3-基]-亚肼基 }- 5-甲基 -2,4-二氢吡 -3-yl]-arylene] } 5-methyl-2,4-dihydropyridyl
H 唑 -3-酮 H oxazol-3-one
5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲 4 基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼 5-{2-hydroxy-3-[Ν'-(1-indan-5-yl-3-methyl-4-yl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indole
XT ΐ 基] -5-甲基苯基 噻吩 -2-羧酸 XT fluorenyl] -5-methylphenyl thiophene-2-carboxylic acid
5-(2-羟基 -3-{Ν'- [3-甲基 -5-氧代 -1-(1 ,1 ,3,3-四甲基茚满 -5-基) -1 ,5-二 5 5-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo-1-(1,1,3,3-tetramethylindan-5-yl)-1,5- Two 5
氢吡唑 -4-亚基] -肼基 }-苯基) -呋喃 Hydropyrazol-4-ylidene]-indenyl}-phenyl)-furan
-2-羧酸 . 2-carboxylic acid.
3'-[Ν'-(1 -双环 [4.2.0]辛垸 -1 ,3,5-三烯 -3-基- 3-甲基 -5-氧代- 1,5-二氢吡唑 6 3'-[Ν'-(1 -Bicyclo[4.2.0]octyl-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole 6
-4-亚基) -肼基 ]-5'-氟 -2'-羟基联苯 -3- 羧酸 -4-subunit)-mercapto]-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid
4-{[2-羟基 -3'-(1Η-四唑 -5-基) -联苯 7 -3-基]-肼叉 2-茚满 -5-基 -5-甲基 4-{[2-hydroxy-3'-(1Η-tetrazol-5-yl)-biphenyl-7-3-yl]-indole 2-indan-5-yl-5-methyl
N- -2,4-二氢吡唑 -3-酮
5-(2-羟基 -3- {Ν'-[3-甲基 -5-氧代 N--2,4-dihydropyrazol-3-one 5-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo
-1 -(5,6,7,8-四氢萘 -2-基) -1,5-二氢吡 -1 -(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyridyl
53 53
唑 -4-亚基] -肼基 } -苯) -2-甲基呋喃 Azole-4-ylidene]-indenyl}-phenyl)-2-methylfuran
-3-羧酸 3-carboxylic acid
5-(2-羟基 -3- {Ν'-[3-甲基 -5-氧代 小(5,6,7，8-四氢萘亚甲基 -2-基) -1 ,5- 5-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo small(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-
54 54
二氢吡唑 -4-並基] -肼基 } -苯基) -呋 喃 -2-羧酸甲酯 Dihydropyrazole-4-mercapto]-indolyl}-phenyl)-furan-2-carboxylic acid methyl ester
5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲 5-{2-hydroxy-3-[Ν'-(1-indan-5-yl-3-yl)
55 基 -5-氧代 -1，5-二氢吡唑 -4-亚基 HI井 基 ]-苯基 呋喃 -2-羧酸甲酯 .Methyl - 5 - oxo - 1 ,5 - dihydropyrazole - 4 - subunit HI well - base - p - phenylfuran - 2 - carboxylate .
3'-{Ν'- [ (2,2-二甲基茚满 -5-基) -3-3'-{Ν'- [ (2,2-Dimethylindan-5-yl)-3-
56 甲基 -5-氧代- 1 ,5-二氢吡唑 -4-亚基] - 肼基 }-2'-羟基联苯 -3-羧酸56 methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl }-2'-hydroxybiphenyl-3-carboxylic acid
4-(2-羟基 -3-{Ν'-[3-甲基 -5-氧代 小(5,6,7,8-四氢萘亚甲基 -2-基)- 1,5-4-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo small(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-
57 57
二氢吡唑 -4-亚基] -肼基 } -苯) -1Η-吡 咯 -2-羧酸 Dihydropyrazole-4-ylidene]-mercapto}-phenyl)-1 Η-pyrrole-2-carboxylic acid
4-{2-羟基 -3-[Ν'-(1 -茚满 -5-基 -3-甲 4-{2-hydroxy-3-[Ν'-(1 - indane-5-yl-3-methyl
58 基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼 基] -苯 }-1Η-吡咯 -2-羧酸 或其药学上可以接受的盐、 水合物或溶剂化合 ( f勿。 进一步， 本发明包括通式 (IA)所示的化合物， 其作为通式 (I)化合物合成的中间体: 58--5-oxo-1,5-dihydropyrazole-4-ylidene-indolyl]-phenyl}-1Η-pyrrole-2-carboxylic acid or a pharmaceutically acceptable salt, hydrate or Solvent compounding (f. Further, the present invention includes a compound represented by the formula (IA) which is an intermediate for the synthesis of the compound of the formula (I):
( I A) ( I A)
其中： among them:
A选自碳原子或氧原子； A is selected from a carbon atom or an oxygen atom;
R5、 和 R7各自独立地选自氢原子、 垸基、 垸氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, a decyloxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
Rs、 R9、 RIG和 Rn各自独立地选自氢原子或垸基； 且 R s , R 9 , R IG and R n are each independently selected from a hydrogen atom or a fluorenyl group;
n是 0， 1或 2。 - 本发明通式 (IA)所示的化合物的优选化合物包括， 但不限于： n is 0, 1 or 2. - Preferred compounds of the compound of the formula (IA) of the present invention include, but are not limited to:
编号 结构 命名 Number structure
2-二环 [4.2.0]辛垸 -1(6),2,4-三烯 2-bicyclo[4.2.0]xin垸-1(6),2,4-triene
1 1
-3-基 -5-甲基 -2,4-二氢吡唑 -3-酮
2-茚满 -5-基 -5-甲基 -2，4-二氢吡唑-3-yl-5-methyl-2,4-dihydropyrazol-3-one 2-indan-5-yl-5-methyl-2,4-dihydropyrazole
2 2
. -3-酮 .-3-ketone
5-甲基 -2-(5,6,7,8-四氢萘 -2-基)- 2,4- 二氢吡唑 -3-酮 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole-3-one
2-(2,3-二氢-苯并呋喃 -5-基) -5-甲基2-(2,3-dihydro-benzofuran-5-yl)-5-methyl
4 or -2，4-二氢吡唑 -3-酮 4 or -2,4-dihydropyrazole-3-one
5-甲基 -2-(3-甲基茚满 -5-基) -2,5-methyl-2-(3-methylindan-5-yl)-2,
5 5
4-二氢吡唑- 3-酮 4-dihydropyrazole-3-one
2-(3-乙基茚满 -5-yl)-5-甲基 -2,42-(3-ethylindan-5-yl)-5-methyl-2,4
6 6
-二氢吡唑 -3-酮 -dihydropyrazole-3-one
2-(3,3-二甲基茚满 -5-基) -5-甲基2-(3,3-dimethylindan-5-yl)-5-methyl
7 7
-2,4-二氢吡唑 -3-酮 -2,4-dihydropyrazole-3-one
2-(2,2-二甲基茚满 -5-基) -5-甲基2-(2,2-dimethylindan-5-yl)-5-methyl
8 8
-2,4-二氢吡唑 -3-酮 -2,4-dihydropyrazole-3-one
5-甲基 -2-(1，1,3,3-四甲基 -茚满 -5-5-methyl-2-(1,1,3,3-tetramethyl-indan-5-
9 9
基) -2,4-二氢吡唑 -3-酮 在本发明的另一个方面是制备中间体 (IA)所示化合物的方法， 包括以下步骤: -2,4-Dihydropyrazol-3-one In another aspect of the invention, a process for the preparation of a compound of the formula (IA), which comprises the steps of:
( I A) ( I A)
氨基取代的苯并多元环与亚硝酸钠在酸性溶液中发生重氮化反应，再通过氯化 亚锡还原得到肼， 肼与亲电的羰基化合物如乙酰乙酸乙酯、 在适宜的溶剂中 (如乙 酸、 乙醇等)加热下缩合得到通式 (IA)化合物。 进一歩， 本发明的另一方面是提供通式化合物 (I)的制备方法， 该方法包括:
The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetoacetate in a suitable solvent ( Condensation under heating, such as acetic acid, ethanol, etc., gives the compound of formula (IA). Further, another aspect of the present invention provides a process for the preparation of the compound (I) of the formula, which comprises:
( I A) ( I ) ( I A) ( I )
通过将取代的苯胺类化合物与亚硝酸钠在适宜的酸性溶液 (如硝酸、 硫酸、 盐 酸） 中进行重氮化反应， 再与通式 (IA)化合物在碱性溶液 (如碳酸氢钠、 碳酸氢钾) 中发生偶联反应得到通式 ω化合物。 本发明涉及通式 (1)和 (ΙΑ)化合物在制备 ΤΡΟ受体激动剂中的用途， By diazotizing a substituted aniline compound with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then reacting a compound of the formula (IA) with an alkaline solution (such as sodium hydrogencarbonate, carbonic acid) A coupling reaction occurs in potassium hydrogen) to give a compound of the formula ω. The present invention relates to the use of the compounds of the formula (1) and (ΙΑ) for the preparation of steroid agonists,
本发明涉及通式 和 (ΙΑ)化合物在制备治疗血小板减少症药物中的用途。 包括 联合使用治疗有效量的选自下列的药物： 集落刺激因子、 细胞因子、 趋化因子、 白细胞介素或细胞因子受体激动剂或拮抗剂、 可溶的受体、 受体激动剂或拮抗剂 抗体或与一个或多个所述药物具有相同的机理而起作用的肽或小分子类。 The present invention relates to the use of a compound of the formula and (ΙΑ) in the manufacture of a medicament for the treatment of thrombocytopenia. Including the combination of a therapeutically effective amount of a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, soluble receptor, receptor agonist or antagonist An antibody or a peptide or small molecule that functions in the same mechanism as one or more of the drugs.
本发明涉及一种药用组合物，其包括药物有效剂量的通式 ω和 (ΐΑ)化合物及其 药学上可以接受的盐、 水合物或溶剂化合物及药学上可接受的盐。 该组合物可以 进一歩含有联合使用的治疗有效量的选自下列的药物： 集落刺激因子、 细胞因子、 趋化因子、 白细胞介素或细胞因子受体激动剂。 该药物组合物在制备治疗血小板 减少症药物的用途。 The present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula ω and (ΐΑ), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable salt. The composition may further comprise a therapeutically effective amount of a drug selected from the group consisting of: a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist. The use of the pharmaceutical composition for the manufacture of a medicament for the treatment of thrombocytopenia.
所述的联合使用包括同时使用或者先后依次使用本发明所述的化合物。 The combined use includes the simultaneous use or sequential use of the compounds described herein.
本发明涉及一种制备含有药用载体或稀释剂和有效量的通式 ω和 (ΙΑ)化合物 及其药学上可以接受的盐、 水合物或溶剂化合物的药物组合物的方法， 该方法包 括将通式 (I)和 (ΙΑ)化合物与药用载体和稀释剂相结合。 发明的详细说明 The present invention relates to a method of preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula ω and (ΙΑ) and a pharmaceutically acceptable salt, hydrate or solvate thereof, the method comprising The compounds of formula (I) and (ΙΑ) are combined with a pharmaceutically acceptable carrier and diluent. Detailed description of the invention
除非有相反陈述， 下列用在说明书和权利要求书中的术语具有下述含义。 "烷基 "指饱和的脂族烃基团， 包括 1至 20个碳原子的直链和支链基团。 优选 含有 1至 10个碳原子的烷基， 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 叔丁基或戊基等。 更优选的是含有 1至 4个碳原子的低级垸基， 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基或叔丁基等。 垸基可以是取代的或未取代的， 当被 取代时， 取代基优选为一个或多个， 独立地选自垸基、 垸氧基、 卤素、 羟基、 氨 基、 硝基、 氰基、 芳基、 杂芳基、 羧酸或羧酸酯。 Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group or the like is preferable. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an indenyl group, a decyloxy group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an aryl group. , heteroaryl, carboxylic acid or carboxylic acid ester.
"芳基"指具有至少一个芳环结构的基团， 即具有共轭的 π电子体系的芳环， 包
括碳环芳基、 杂芳基和联芳基。 块基可以是取代的或未取代的， 当被取代时， 取 代基优选为一个或多个， 独立地选自烷基、 烷氧基、 卤素、 羟基、 氨基、 硝基、 氰基、 芳基、 杂芳基、 羧酸或羧酸酯。 "Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, Carbocyclic aryl, heteroaryl and biaryl. The block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. , heteroaryl, carboxylic acid or carboxylic acid ester.
"杂芳基"指具有 1至 4个杂原子作为环原子， 其余的环原子为碳的芳基， 杂原 子包括氧、 硫和氮。 所述环可以是 5元或 6元环。 杂芳基基团的实例包括呋喃基、 噻吩基、 吡啶基、 吡咯、 N-垸基吡咯基、 嘧啶基、 吡嗪基、 咪唑基、 四唑基等。 杂芳基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个， 独立 地选自烷基、 烷氧基、 卤素、 羟基、 氨基、 硝基、 氰基、 芳基、 杂芳基、 羧酸或 羧酸酯。 "Heteroaryl" means an aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and hetero atoms including oxygen, sulfur and nitrogen. The ring may be a 5- or 6-membered ring. Examples of the heteroaryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-fluorenylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. Base, heteroaryl, carboxylic acid or carboxylic acid ester.
"羟基 "指 -OH基团。 "Hydroxy" means an -OH group.
"烷氧基"指 -0- (烷基)和 -0- (未取代的环烷基)。 代表性实例包括但不限于甲氧 基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环丁氧基、 环戊氧基、 环己氧基等。 垸氧基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个， 独立 地选自垸基、 垸氧基、 卤素、 羟基、 氨基、 硝基、 氰基、 芳基、 杂芳基、 羧酸或 羧酸酯。 "Alkoxy" means -0-(alkyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The methoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an indenyl group, a decyloxy group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an aromatic group. Base, heteroaryl, carboxylic acid or carboxylic acid ester.
"卤素"指氟、 氯、 溴或碘。 "Halogen" means fluoro, chloro, bromo or iodo.
"氨基 "指 -NH2。 "Amino" means -NH 2 .
"氰基 "指 -CN。 "Cyano" means -CN.
"硝基 "指 -N02。 "Nitro" means -N0 2 .
"烷氧基"指 -0- (烷基)。 "Alkoxy" means -0-(alkyl).
"羧酸 "指 (綜基) C(=0)OH。 "Carboxylic acid" means (healdyl) C(=0)OH.
"羧酸酯"指 (烷基) C(=0)0 (垸基）。 "Carboxylic ester" means (alkyl) C(=0)0 (fluorenyl).
"药物组合物 "表示一种或多种本文所述化合物或其生理学上 /药学上可接受 的盐或前体药物与其他化学组分的混合物， 其他组分例如生理学 /药学上可接受的 载体和赋形剂。 药物组合物的目的是促进化合物对生物体的给药。 . 本发明化合物的合成方法 "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Method for synthesizing the compound of the present invention
为了完成本发明的目的， 本发明采用如下技术方案: In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
( I A) ( I A)
氨基取代的苯并多环与亚硝酸钠在酸性溶液中进行重氮化反应，再通过氯化亚 锡还原得到肼，肼与亲电的羰基化合物如乙酰乙酸乙酯、在适宜的溶剂中 (如乙酸、
乙醇等)加热下缩合得到通式 (IA)化合物。 流程图 II The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetoacetate in a suitable solvent ( Such as acetic acid, Ethanol or the like is condensed under heating to give a compound of the formula (IA). Flowchart II
将取代的苯胺类化合物与亚硝酸钠在适宜的酸性溶液 (如硝酸、 硫酸、 盐酸)中 重氮化， 再与通式 (IA)化合物在碱性溶液 (如碳酸氢钠、 碳酸氢钾)中发生偶联反应 得到通式 (I)化合物。 Diluting the substituted aniline compound with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then reacting the compound of formula (IA) with an alkaline solution (such as sodium bicarbonate, potassium bicarbonate) The coupling reaction takes place to give a compound of the formula (I).
具体实施方式 detailed description
以下结合实施例用于进一歩描述本发明， 但这些实施例并非限制着本发明的 范围。 The invention is described below in conjunction with the examples, but these examples are not intended to limit the scope of the invention.
实施例
化合物的结构是通过核磁共振 (iHNMR)或质谱 (MS)来确定的。 'HNMR位移 (δ) 以百万分之一 (ppm)的单位给出。 1HNMR的测定是用 Bruker AVANCE-400核磁仪， 测定溶剂为氘代甲醇 (CD3OD)、 氘代氯仿 (CDC13)， 六氘代二甲基亚砜 (DMSO-d6) 内标为四甲基硅垸 (TMS)， 化学位移是以 10—6(pprr作为单位给出； Example The structure of the compound is determined by nuclear magnetic resonance (iH NMR) or mass spectrometry (MS). The 'HNMR shift (δ) is given in parts per million (ppm). The 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDC1 3 ), and hexamethyl dimethyl sulfoxide (DMSO-d6) was internally labeled as four embankment silicon group (TMS), chemical shifts are 10- 6 (pprr as given in units;
MS的测定用 FINNIGAN LCQAd (ESI)质谱仪 (生产商： Therm,型号： Finnigan LCQ advantage MAX; For the determination of MS, FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX;
IC50值的测定用. NovoStar酶标仪 (德国 BMG .公司）； Determination of IC 50 value. NovoStar microplate reader (BMG, Germany);
薄层硅胶使用烟台黄海 HSGF254或青岛 GF254硅胶板； Thin layer of silica gel using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate;
硅胶柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体； Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as carrier;
HPLC测试使用安捷伦 1200DAD高压液相色谱仪 (Sunfire C18 150><4.6mm色谱 柱)和 Waters 2695-2996高压液相色谱仪 (Gimini C18 150x4.6mm色谱柱） The HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150><4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
加压氢化反应使用 Pau 3916EKX型氢化仪和清蓝 QL型氢气发生器；微波反应 使用 CEM Discover-S 908860型微波反应器； The pressurized hydrogenation reaction uses a Pau 3916EKX hydrogenation apparatus and a clear blue QL type hydrogen generator; the microwave reaction uses a CEM Discover-S 908860 microwave reactor;
实施例中无特殊说明， 反应均在氮气氛下进行； Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen atmosphere;
氮气氛是指反应瓶连接一个约 1L容积的氮气气球； The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
氢气氛是指反应瓶连接一个约 1L容积的氢气气球； The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
实施例中无特殊说明， 反应中的溶液是指水溶液； Unless otherwise specified in the examples, the solution in the reaction means an aqueous solution;
. TLC是指薄层色谱。 实施例 1 TLC refers to thin layer chromatography. Example 1
2'-羟基 -3'-ΓΝ'-ίί-節满- 5-基 -3-甲基 -5-氧代 -1,5-二氢 [¾ -4-亚基) -肼基 1-联苯基 -3-羧 2'-Hydroxy-3'-ΓΝ'-ίί-Frozen- 5-yl-3-methyl-5-oxo-1,5-dihydro[3⁄4-4-ylidene]-indenyl 1-linked Phenyl-3-carboxylate
2-溴 -6-硝基苯酚 2-bromo-6-nitrophenol
.将.60 mL浓硫酸稀释到 186 mL水中， 冷却至室温后加入硝酸钠 (79.2 g, 0.932 mol), 保持 25°C以下， 滴加邻溴苯酚 la(60 mL, 0.516 mol)， 室温反应 2小时。 TLC
跟踪至原料消失， 加入 320mL乙酸乙酯溶解析出的固体， 分别用水和饱和氯化钠 溶液洗涤， 用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得 残余物， 得到标题产物 2-溴 -6-硝基苯酚 lb(48.2 g， 黄色固体)。 产率： 42.8%。 MS m/z(ESI): 218[M+1] Dilute .60 mL of concentrated sulfuric acid into 186 mL of water, cool to room temperature, add sodium nitrate (79.2 g, 0.932 mol), keep below 25 °C, add o-bromophenol la (60 mL, 0.516 mol), and react at room temperature. 2 hours. TLC After the disappearance of the starting material, the precipitated solid was dissolved in ethyl acetate (3 mL), and the residue was evaporated, evaporated, evaporated, evaporated The title product 2-bromo-6-nitrophenol lb (48.2 g, yellow solid). Yield: 42.8%. MS m/z (ESI): 218 [M+1]
'HNMR(400MHZ, CDCb): 56.88-7.02(m, IH), 7.89-7.91(d, J=8Hz, IH), 8.12-8.15(m, IH), 11.18(s, IH) 第二步 'HNMR (400MHZ, CDCb): 56.88-7.02(m, IH), 7.89-7.91 (d, J=8Hz, IH), 8.12-8.15(m, IH), 11.18(s, IH)
1-溴 -2-甲氧基 -3-硝基苯 1-bromo-2-methoxy-3-nitrobenzene
将 2-溴 -6-硝基苯酚 lb(46.55 g, 0.214 mol)溶解于 500 mL丙酮中， 加入碳酸钾 Dissolve 2-bromo-6-nitrophenol lb (46.55 g, 0.214 mol) in 500 mL of acetone and add potassium carbonate.
(35.36 g, 0.256 mol)和碘甲垸 (20.1 mL, 0.32 mol), 70°C加热回流 40小时。 TLC跟 踪至原料消失， 减压浓缩， 加入 1300 mL乙酸乙酯和 500 mL水， 水相用乙酸乙酯 萃取 (300mLx2)， 合并有机相， 分别用 4N盐酸和饱和碳酸氢钠溶液洗涤， 用无水 硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题 产物 1-溴 -2-甲氧基 -3-硝基苯 lc(44.59 g， 棕色固体)。 产率： 90.0%。 (35.36 g, 0.256 mol) and iodoformamidine (20.1 mL, 0.32 mol), heated at 70 ° C for 40 hours. TLC was traced to disappearance of the starting material, concentrated under reduced pressure, 1300 mL of ethyl acetate and 500 mL of water were added, and the aqueous phase was extracted with ethyl acetate (300 mL×2), and the organic phases were combined and washed with 4N hydrochloric acid and saturated sodium hydrogen carbonate solution, respectively. The residue was dried over EtOAc EtOAc EtOAc. Yield: 90.0%.
MS mix (ESI): 234[M+1] 第三歩 MS mix (ESI): 234[M+1] third
2'-甲氧基 -3'-硝基联苯基 -3-羧酸 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid
将 1-溴 -2-甲氧基 -3-硝基苯 lc (23.25 g, 0.10 mol)、3-羧基苯基硼酸 (19.5 g, 0.117 mol)和四 (三苯基膦)钯 (8.86 g, 7.7 mol)溶解于 100 mL 2N碳酸钠溶液和 500 mLl,4- 二氧六环的混和溶剂中， 105°C加热回流 43小时。 TLC跟踪至原料消失， 减压浓 缩， 加入 300 mL 6N 盐酸溶液和 400 mL 乙酸乙酯， 水相用乙酸乙酯萃取 (200 mLx2), 合并有机相， 用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 得到标题产物 2'-甲氧基 -3'-硝基联苯基 -3-羧酸 ld(53.93 g， 浅黄色固体)。 1-Bromo-2-methoxy-3-nitrobenzene lc (23.25 g, 0.10 mol), 3-carboxyphenylboronic acid (19.5 g, 0.117 mol) and tetrakis(triphenylphosphine)palladium (8.86 g) , 7.7 mol) was dissolved in a mixed solvent of 100 mL of 2N sodium carbonate solution and 500 mL of 1,4-dioxane, and heated under reflux at 105 ° C for 43 hours. The TLC was traced to the disappearance of the starting material, and concentrated under reduced pressure. EtOAc (3 mL), EtOAc (EtOAc) Concentration by pressure gave the title product 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid ld (53.93 g, pale yellow solid).
MS m/z (ESI): 272[M-1] MS m/z (ESI): 272 [M-1]
1HNMR(400MHz, CDC13): 53.44-3.46(d, J=8Hz,3H), 7.42-7.46(m, IH), 7.63-7.67(m, IH), 7.21-7.75(m, IH), 7.82-7.84(m, IH), 7.90-7.92(m, IH), 8.01-8.03(d, J=8Hz, IH), 8.11(s, IH) 第四步 1H NMR (400MHz, CDC1 3 ): 53.44-3.46 (d, J=8Hz, 3H), 7.42-7.46 (m, IH), 7.63-7.67 (m, IH), 7.21-7.75 (m, IH), 7.82- 7.84(m, IH), 7.90-7.92(m, IH), 8.01-8.03(d, J=8Hz, IH), 8.11(s, IH) Step 4
2'-甲氧基 -3'-氨基联苯基 -3-羧酸 2'-methoxy-3'-aminobiphenyl-3-carboxylic acid
将 2'-甲氧基 -3'-硝基联苯基 -3-羧酸 Id (0.48 g, 1.74 mmol)溶解于 60 mL乙醇中， 加入 0.5g钯-碳和甲酸铵 (U g, 17.4mmol)， 80°C加热回流 20分钟。 TLC跟踪至原 枓消失， 过滤， 滤液减压浓缩， 干燥， 得到标题产物 2'-甲氧基 -3'-氨基联苯基 -3- 羧酸 le(0.42 g， 白色固体)。 产率： 93.3%。 2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid Id (0.48 g, 1.74 mmol) was dissolved in 60 mL of ethanol, and 0.5 g of palladium-carbon and ammonium formate (U g, 17.4) was added. Methyl), heated to reflux at 80 ° C for 20 minutes. The TLC was traced to dryness of EtOAc (EtOAc). Yield: 93.3%.
MSm/z(ESl): 242 [M-1]
第五歩 MSm/z(ESl): 242 [M-1] Fifth
3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide
将 2'-甲氧基 -3'-氨基联苯基 -3-羧酸 le (2.5 g, 10.3 mmol)溶解于 100 mL氢溴酸 溶液 (40%)中， 120Ό加热回流过夜。 TLC跟踪至原料消失， 减压浓缩， 用硅胶柱 色谱法纯化所得残余物， 得到标题产物 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 lf(2.4 g， 土黄色固体)， 产率： 88.8%。 2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid le (2.5 g, 10.3 mmol) was dissolved in 100 mL of hydrobromic acid solution (40%) and heated to reflux overnight. TLC was traced to the disappearance of the starting material, and the residue was evaporated to ethylamine. Yellow solid), Yield: 88.8%.
MS m/z (ESI): 230[M+1] MS m/z (ESI): 230 [M+1]
[注： 参考文献： WO0189457] [Note: References: WO0189457]
第六歩 Sixth
5-肼基茚满 5-肼基茚满
冰浴下将 5-氨基茚满 lg (3.59 g, 27.0 mmol)溶解于 20 mL浓盐酸中， 搅拌 10 分钟。 滴加入 10 mL亚硝酸钠溶液 (1.86 g, 27.0 mmol), 冰浴下继续搅拌 15分钟备 用。 5-Aminoindan lg (3.59 g, 27.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min. 10 mL of sodium nitrite solution (1.86 g, 27.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.
冰盐浴下将二水合氯化亚锡 (24.4 g, 108.0 mmol)溶解于 10 mL浓盐酸中， 将备 用中间体溶液加入其中， 升至室温反应 1.5小时。 冰浴下用 40%氢氧化钠溶液调 pH至 9， 加入 400 mL乙酸乙酯萃取， 减压浓缩， 干燥， 得到标题产物 5-肼基茚 满 lh(2.05 g， 红棕色固体)。 产率： 51.3%。 The stannous chloride dihydrate (24.4 g, 108.0 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice salt bath, and the intermediate solution was added thereto, and the mixture was allowed to react to room temperature for 1.5 hours. The mixture was adjusted to pH 9 with 40% EtOAc EtOAc (EtOAc)EtOAc. Yield: 51.3%.
MS m/z (ESI): 149[M+1] 第七歩 MS m/z (ESI): 149 [M+1] seventh
2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 2-indan-5-yl-5-methyl-2,4-dihydropyrazole-3-one
将 5-肼基茚满 lh (2.05 g, 13.8 mmol)溶解于 50mL乙酸中， 加入乙酰乙酸乙酯 (1.76 mL, 13.8 mmol), 加热至 100°C过夜。 TLC跟踪至原料消失， 减压浓缩， 用硅 胶柱色谱法纯化所得残余物， 得到标题产物 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li(1.84 g, 黄色固体)。 产率： 62.3%。 5-Mercaptopurpurin lh (2.05 g, 13.8 mmol) was dissolved in 50 mL of ethyl acetate. ethyl acetoacetate (1.76 mL, 13.8 mmol) was added and the mixture was warmed to 100 ° C overnight. TLC was traced to the disappearance of the material, and the residue was evaporated to dryness. (1.84 g, yellow solid). Yield: 62.3%.
MS m/z (ESI): 215[M+1] MS m/z (ESI): 215 [M+1]
'HNMR(400MHz, CDC13): 57.69(s, 1H), 7.60(d, J=8.0Hz, 1H), 7.24(d, J=8Hz, 1H), 3.44(s, 2H), 2.90-2.97(m, 4H), 3.2 l(s, 3H), 2.07-2.14(m, 2H)。 第八歩 'HNMR (400MHz, CDC1 3 ): 57.69(s, 1H), 7.60(d, J=8.0Hz, 1H), 7.24(d, J=8Hz, 1H), 3.44(s, 2H), 2.90-2.97( m, 4H), 3.2 l(s, 3H), 2.07-2.14 (m, 2H). Eighth
2'-轻基 -3'-[Ν'- ( 茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 ]-联苯基 -3-羧 酸 2'-light base-3'-[Ν'-(indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]- Biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (267 mg, 1.16 mmol)溶解于 10 mL盐酸 (IN) 中， 滴加入 10 mL亚硝酸钠溶液 (88 mg, 1.28 mmol)的， 再加入 2- 茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (249 mg, 1.16 mmol), 用饱和碳酸氢钠溶液 将反应液 pH调至 8， 加入 10 mL乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过
滤， 干燥， 用甲醇重结晶， 得到标题产物 2'-羟基 -3'-[Ν'-(1-茚满 -5-基 -3-甲基 -5-羰基 -1 ,5-二氢吡唑 -4-亚基) -肼基]-联苯基 -3-羧酸 1(60 mg, 黄色固体)。 产率： 11.4%。 MS m/z (ESI): 453[M-1] 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (267 mg, 1.16 mmol) was dissolved in 10 mL of hydrochloric acid (IN) under ice bath, and 10 mL of sodium nitrite was added dropwise. Solution (88 mg, 1.28 mmol) followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (249 mg, 1.16 mmol). The pH of the reaction solution was adjusted to 8 with a sodium hydrogen solution, 10 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. TLC traces to the disappearance of raw materials, Filtration, drying, recrystallization from methanol gave the title product 2'-hydroxy-3'-[Ν'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyridyl Imidazole-4-ylidene]-indenyl]-biphenyl-3-carboxylic acid 1 (60 mg, yellow solid). Yield: 11.4%. MS m/z (ESI): 453 [M-1]
'HNMR(400MHz, DMSO-i¾: 62.03-2.10(m, 2H), 2.34 (s, 3H)， 2.86-2.93(m, 4H)， 7.13-7.17(m, 2H), 7.28-7.30(d, J = 8.1Hz, 1H), 7.60-7.82(m, 5H), 7.96-7.98 (d, J = 8.1 Hz, 1H)， 8.13 (s, 1H), 9.66 (s, 1H), 13.03 (s, 1H), 13.76 (s, 1H)0 'HNMR (400 MHz, DMSO-i3⁄4: 62.03-2.10 (m, 2H), 2.34 (s, 3H), 2.86-2.93 (m, 4H), 7.13-7.17 (m, 2H), 7.28-7.30 (d, J = 8.1 Hz, 1H), 7.60-7.82 (m, 5H), 7.96-7.98 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 9.66 (s, 1H), 13.03 (s, 1H) , 13.76 (s, 1H) 0
实施例 2 Example 2
第一步 First step
2-溴 -4-氟 -6-硝基苯酚 2-bromo-4-fluoro-6-nitrophenol
冰盐浴下将 2-溴 -4-氟 -苯酚 2a(8.0 g, 41.9 mmol)溶解于 10 mL硫酸溶液 (50%) 中， 滴加入硝酸钠 (7.1 g, 83.5 mmol)的 24 mL硫酸溶液 (25 %)， 室温反应 1.5小时。 TLC跟踪至原料消失， 加入 50 mL水， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 乙酸乙酯层分别用水和饱和碳酸氢钠溶液洗涤， 用无水硫酸镁干燥， 过滤， 滤液 减压浓缩， 得到标题产物 2-溴 -4-氟 -6-硝基苯酚 2b(8.0 g， 红色固体)， 直接用于下 一步反应， 产率： 80.8%。 第二步 2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid solution (50%) in an ice salt bath, and sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid solution was added dropwise. (25%), reacted at room temperature for 1.5 hours. TLC was traced to the disappearance of the starting material, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was combined, and the ethyl acetate layer was washed with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, filtrate reduced Concentration by pressure gave the title product 2-bromo-4-fluoro-6-nitrophenol 2b (8.0 g, EtOAc). Second step
1-溴 -5-氟 -2-甲氧基 -3-硝基苯 1-bromo-5-fluoro-2-methoxy-3-nitrobenzene
将 2-溴 -4-氟 -6-ϊί肖基苯酚 2b (24.7 g, 104.7 mmol)和碳酸钾（17.34 g, 125.6 mmol) 溶解于 300 mL丙酮中， 快速加入碘甲垸 (9.8 mL, 157.1 mmol), 80°C加热回流 22
小时。 TLC跟踪至原料消失， 减压浓缩， 加入 200 mL乙酸乙酯和 200 mL水， 水 相用乙酸乙酯萃取 (100 mLx2)， 合并有机相， 分别用 4N盐酸和饱和碳酸氢钠溶液 洗涤， 用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余 物，得到标题产物 1 -溴 -5-氟 -2-.甲氧基 -34肖基苯 2c(16.18 g，白色固体)。产率： 61.8%。 MS m/z (ESI): 252[M+1] 2-Bromo-4-fluoro-6-indolylphenol 2b (24.7 g, 104.7 mmol) and potassium carbonate (17.34 g, 125.6 mmol) were dissolved in 300 mL of acetone, and methyl iodide (9.8 mL, 157.1) was added quickly. Mm), heated at 80 ° C reflux 22 hour. TLC was traced to the disappearance of the starting material, concentrated under reduced pressure, ethyl acetate (200 mL) and water (200 mL) were added, and the aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phases were combined and washed with 4N hydrochloric acid and saturated sodium hydrogen carbonate solution respectively. The residue was dried over anhydrous MgSO.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid). Yield: 61.8%. MS m/z (ESI): 252 [M+1]
'H NMR (CDC13): δ 3.99(s, 3H), 7.81 (d, J = 8.0Hz, 1H)， 7.28 (q, J = 8.0Hz, 4.0Hz, 1 H) 7.89 (q, J = 8.0Hz, 4.0Hz, 1H)。 第三歩 'H NMR (CDC1 3 ): δ 3.99(s, 3H), 7.81 (d, J = 8.0Hz, 1H), 7.28 (q, J = 8.0Hz, 4.0Hz, 1 H) 7.89 (q, J = 8.0 Hz, 4.0Hz, 1H). Third
5'-氟 -2'-甲氧基 -3'-硝基联苯基 -3-羧酸 5'-fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid
将 1-溴 -5-氟 -2-甲氧基 -3-硝基苯 2c (16.18 g， 64.7 mmol)、3-羧基苯基硼酸 (13.88 g, 77.7 mmol)和四 (三苯基膦)钯 (3.73 g, 3.2 mmol)溶解于 65 mL碳酸钠溶液 (2N) 和 300 mLl ,4-二氧六环的混和溶剂中， 120°C加热回流 24小时。 TLC跟踪至原料 消失， 减压浓缩， 加入 150 mL盐酸溶液 (6N)和 200 mL乙酸乙酯， 水相用乙酸乙 酯萃取 (100 mLx2)， 合并有机相， 用无水硫酸镁干燥， 过滤， 滤液减压浓缩， .得到 标题产物 5'-氟 -2'-甲氧基 -3'-硝基联苯基 -3-羧酸 2d(7.86 g，黄色固体)。产率： 41.7%。 MS m/z (ESI): 290[M-1] 第四步 1-Bromo-5-fluoro-2-methoxy-3-nitrobenzene 2c (16.18 g, 64.7 mmol), 3-carboxyphenylboronic acid (13.88 g, 77.7 mmol) and tetrakis(triphenylphosphine) Palladium (3.73 g, 3.2 mmol) was dissolved in a mixed solvent of 65 mL of sodium carbonate solution (2N) and 300 mL of 4-dioxane, and heated to reflux at 120 ° C for 24 hours. TLC was traced to the disappearance of the starting material, and the residue was evaporated. EtOAc (EtOAc) (EtOAc) The filtrate was concentrated under reduced pressure to give the title product, 5,-fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (7.86 g, yellow solid). Yield: 41.7%. MS m/z (ESI): 290 [M-1] Step 4
3'-硝基 -5'-氟 -2'-羟基联苯基 -3-羧酸 3'-Nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid
将 5'-氟 -2'-甲氧基 -3'-硝基联苯基 -3-羧酸 2d (2.91 g, 10.0 mmol) 溶解于 10 mL 氢溴酸溶液 (40%)中， 120°C加热回流过夜。 TLC跟踪至原料消失， 减压浓缩， 用 硅胶柱色谱法纯化所得残余物， 得到标题产物 3'-硝基 -5'-氟 -2'-羟基联苯基 -3-羧酸 2e(2.38 g, 黄色固体)， 直接用于下一歩反应。 产率： 85.7%。 Dissolve 5'-fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (2.91 g, 10.0 mmol) in 10 mL hydrobromic acid solution (40%), 120° C was heated to reflux overnight. TLC was traced to the disappearance of the starting material, and the residue was evaporated to ethylamine. , yellow solid), used directly in the next reaction. Yield: 85.7%.
MS m/z (ESI): 277[M-1] 第五歩 MS m/z (ESI): 277[M-1] fifth
3'-氨基 -5'-氟 -2'-羟基联苯基 -3-羧酸 3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid
将 3'-硝基 -5'-氟 -2'-羟基联苯基 -3-羧酸氢溴酸盐 2e (417 mg， 1.5 mmol)溶解于 60 mL乙醇中，加入 0.5g钯-碳和甲酸铰 (0.95 g, 1.5 mmol), 80°C加热回流 20分钟。 TLC跟踪至原料消失， 过滤， 减压浓缩， 干燥， 得到标题产物 3'-氨基 -5'-氟 -2'-羟 基联苯基 -3-羧酸 2f(339 mg， 紫红色固体)。 产率： 91.5%。 Dissolve 3'-nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 2e (417 mg, 1.5 mmol) in 60 mL of ethanol and add 0.5 g of palladium-carbon and Formic acid hinge (0.95 g, 1.5 mmol) was heated to reflux at 80 ° C for 20 min. TLC was traced to the disappearance of the material, which was filtered, concentrated under reduced pressure and dried to give the title product 3'-amino -5'-fluoro- 2'-hydroxybiphenyl-3-carboxylic acid 2f (339 mg, m. Yield: 91.5%.
MS m/z (ESI): 246[M-1] 第六歩 MS m/z (ESI): 246 [M-1] sixth
5'-氟 -2'-羟基 -3'-[N'-(l -茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基]-联苯基 5'-Fluoro-2'-hydroxy-3'-[N'-(l-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene )-mercapto]-biphenyl
-3-羧酸
冰浴下将 3'-氨基 -5'-氟 -2'-羟基联苯基 -3-羧酸 2f (296 mg, 1.20 mmol)溶解于 10mL盐酸 (IN)中， 滴加入 10mL亚硝酸钠溶液 (91 mg, 1.32 mmol), 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (257 mg, 1.20 mmol), 用饱和碳酸氢钠溶液将反 应液 pH调至 8， 加入 lO niL乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过滤， 干燥， 用甲醇重结晶， 得到标题产物 5'-氟 -2'-羟基 -3'-[Ν'-(1 -茚满 -5-基 1-3-甲基 -5- 氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基] -联苯基 -3-羧酸 2(87 mg,红色固体)。产率： 14.1%。 MS m/z (ESI): 471 [M-1] 3-carboxylic acid 3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (296 mg, 1.20 mmol) was dissolved in 10 mL of hydrochloric acid (IN) under ice bath, and 10 mL of sodium nitrite solution was added dropwise. (91 mg, 1.32 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (257 mg, 1.20 mmol) with sat. sodium bicarbonate The solution was adjusted to pH 8 and added to 10 mL of ethanol and allowed to warm to room temperature overnight. TLC was traced to disappearance of the starting material, filtered, dried and recrystallized from methanol to give the title product 5'-fluoro-2'-hydroxy-3'-[Ν'-(1 - indane-5-yl 1-3-methyl -5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-biphenyl-3-carboxylic acid 2 (87 mg, red solid). Yield: 14.1%. MS m/z (ESI): 471 [M-1]
'HNMR(400MHz, DMS0-d6): δ 2.02(m, 2H), 2.34(s, 3H), 2.87(m, 4H), 7.03(dd, Jl=9.2Hz, J2=2.8Hz, IH), 7.28(d, J=8.0Hz, IH), 7.48(m, IH), 7.6 l(m, 2H), 7.76(s, IH), 7.83(d, J=7.6Hz, IH), 7.98(d, J=8.0Hz, IH), 8.17(s, IH), 9.59(s, IH), 13.03(s, IH), 13.62(s, IH) ' 'HNMR (400MHz, DMS0-d6): δ 2.02(m, 2H), 2.34(s, 3H), 2.87(m, 4H), 7.03 (dd, Jl=9.2Hz, J2=2.8Hz, IH), 7.28 (d, J=8.0Hz, IH), 7.48(m, IH), 7.6 l(m, 2H), 7.76(s, IH), 7.83(d, J=7.6Hz, IH), 7.98(d, J =8.0Hz, IH), 8.17(s, IH), 9.59(s, IH), 13.03(s, IH), 13.62(s, IH) '
实施例 3 Example 3
2'-羟基- 3 N'-「3-甲基- 5-氧代小 (5.6,7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基 1-肼基 联苯基 -3-羧酸 2'-hydroxy-3 N'-"3-methyl-5-oxo small (5.6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene 1 -mercaptobiphenyl-3-carboxylic acid
第一步 First step
2-肼基 -5,6,7,8-四 2-mercapto -5,6,7,8-four
冰浴下将 2-氨基 -5,6，7,8-四氢萘 3g (3.68 g, 25.0 mmol)溶解于 20 mL浓盐酸中， 搅拌 10分钟。滴加入 10 mL亚硝酸钠溶液 (1.72 g, 25.0 mmol),冰浴下继续搅拌 15 分钟备用。 2-Amino-5,6,7,8-tetrahydronaphthalene 3g (3.68 g, 25.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min. 10 mL of sodium nitrite solution (1.72 g, 25.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.
冰盐浴下将二水合氯化亚锡 (22.6 g, 100 mmol)溶解于 10 mL浓盐酸中，将备用 中间体溶液加入其中， 升至室温反应 1.5小时。 冰浴下用 40%氢氧化钠溶液调 pH 至 9， 加入 400 mL乙酸乙酯萃取， 减压浓缩， 干燥， 得到标题产物 2-肼基 -5,6,7,8- 四氢萘 3h(2.19 g， 黄色油状液体)。 产率： 53.7%。 The stannous chloride dihydrate (22.6 g, 100 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice-salt bath, and the intermediate intermediate solution was added thereto, and the mixture was allowed to react to room temperature for 1.5 hours. The mixture was adjusted to pH 9 with a 40% aqueous sodium hydroxide solution, and extracted with ethyl acetate (400 mL). 2.19 g, yellow oily liquid). Yield: 53.7%.
MS m/z (ESI): 163[ +1] 第二步
5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 将 2-肼基- 5,6,7,8-四氢萘 3h (2.0 g, 12.3 mmol)溶解于 50 mL乙酸中， 再加入乙 酰乙酸乙酯 (1.57 mL, 12.3 mmol), 加热至 100°C过夜。 TLC跟踪至原料消失， 减压 浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 5-甲基- 2-(5,6,7,8-四氢萘 -2- 基) -2,4-二氢吡唑 -3-酮 3i(1.58 g， 无色油状液体)。 产率： 56.2%。 MS m/z (ESI): 163[ +1] second step 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 2-mercapto-5-6,7,8 - Tetrahydronaphthalene 3h (2.0 g, 12.3 mmol) was dissolved in 50 mL of ethyl acetate. ethyl acetoacetate (1.57 mL, 12.3 mmol) was then added and then warmed to 100 ° C overnight. TLC was traced to the disappearance of the starting material, and the residue was evaporated to silica gel column chromatography to afford the title product 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2. 4-Dihydropyrazol-3-one 3i (1.58 g, colorless oily liquid). Yield: 56.2%.
MS m/z (ESI): 457[2M+1] MS m/z (ESI): 457 [2M+1]
'HNMR(CDC13): 87.54-7.58(m, 2H), 7.08-7.10(d, J=8Hz, IH), 3.43(s, 2H), 'HNMR(CDC1 3 ): 87.54-7.58 (m, 2H), 7.08-7.10 (d, J=8Hz, IH), 3.43(s, 2H),
62.77-2.81(m, 4H), 2.21(s, 3H), 1.80-1.83(m, 4H). 第三步 62.77-2.81(m, 4H), 2.21(s, 3H), 1.80-1.83(m, 4H). Step 3
2'-羟基 -3'-{N'-[3-甲基 -5-氧代 -l-(5,6,7,8-四氢萘 -2-基) -1，5-二氢吡唑 -4-亚基] -肼基 联苯基 -3-羧酸 2'-Hydroxy-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyridyl Azole-4-ylidene]-mercaptobiphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (250 mg, 1.09 mmol)溶解于 10 mL盐酸 (IN)中， 滴加入 10 mL亚硝酸钠溶液 (82 mg, 1.2 mmol), 再加入 5-甲基 ,-2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (249 mg, 1.09 mmol), 用饱和碳酸氢 钠溶液将反应液 pH调至 8， 加入 10 mL乙醇， 升至室温过夜。 TLC跟踪至原料消 失， 过滤， 干燥， 用甲醇重结晶， 得到标题产物 2'-羟基 -3'-{N'-[3-甲基 -5-氧代 -1-(5,6,7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基] -肼基 联苯基 -3-羧酸 3(59 mg, 黄色 固体)。 产率： 11.6%。 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (250 mg, 1.09 mmol) was dissolved in 10 mL of hydrochloric acid (IN) under ice bath, and 10 mL of sodium nitrite was added dropwise. Solution (82 mg, 1.2 mmol) followed by 5-methyl,-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3i (249 mg, 1.09 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and then added to 10 mL of ethanol and allowed to warm to room temperature overnight. TLC was traced to the disappearance of the starting material, filtered, dried and recrystallized from methanol to give the title product 2'-hydroxy-3'-{N'-[3-methyl-5-oxo-1-(5,6,7, 8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-mercaptobiphenyl-3-carboxylic acid 3 (59 mg, yellow solid). Yield: 11.6%.
MS m/z (ESI): 467[M-1] MS m/z (ESI): 467 [M-1]
'HNMR(400MHz, DMSO-d6): δ 1.75(m, 4H), 2.33(s, 3H), 2.70(m, 4H), 7.13(m, 3H), 7.36(m, IH), 7.60(m, 2H), 7.7 l(m, IH), 7.75(m, IH), 7.97(d, J=7.6Hz, IH), 8.14(s, 1H): 9.66(s, IH), 13.03(br, IH), 13.76(s, IH) 实施例 4 'HNMR (400MHz, DMSO-d6): δ 1.75 (m, 4H), 2.33 (s, 3H), 2.70 (m, 4H), 7.13 (m, 3H), 7.36 (m, IH), 7.60 (m, 2H), 7.7 l(m, IH), 7.75(m, IH), 7.97(d, J=7.6Hz, IH), 8.14(s, 1H) : 9.66(s, IH), 13.03(br, IH) , 13.76(s, IH) Example 4
5'-氟 -2'-羟基 -3'4N'-「3-甲基 -5-氧代 -l-(5，6,7,8-四氢萘 -2-基 1.5-二氢吡唑 -4-亚基 肼基 }-联苯基 -3-羧酸 5'-Fluoro-2'-hydroxy-3'4N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl 1.5-dihydropyrazole -4-indolyl}-biphenyl-3-carboxylic acid
MS m/z (ESI): 485 [M-l] MS m/z (ESI): 485 [M-l]
'HNMR(400MHz, DMSO-i 6): δ 1.74(m, 4H)， 2.33(s, 1H), 2.73(m, 4H), 7.02(dd, Jl=9.2Hz, J2=2.0Hz, 1 H), 7.11 (d， d=8.0Hz, 1H), 7.47(m, 1H), 7.63(m, 3H), 7.82(d J=7.6Hz, 1 H), 7.98(d, J=7.6Hz, 1H), 8.18(s, 1H), 9.58(s, 1H), 13.05(s, 1H), 13.62(s, 1H) 实施例 5 'HNMR (400MHz, DMSO-i 6): δ 1.74 (m, 4H), 2.33 (s, 1H), 2.73 (m, 4H), 7.02 (dd, Jl = 9.2 Hz, J2 = 2.0 Hz, 1 H) , 7.11 (d, d=8.0Hz, 1H), 7.47(m, 1H), 7.63(m, 3H), 7.82(d J=7.6Hz, 1 H), 7.98(d, J=7.6Hz, 1H) , 8.18(s, 1H), 9.58(s, 1H), 13.05(s, 1H), 13.62(s, 1H) Example 5
3'-Γ '-Π -双环『4.2.01 辛垸 -1ί6),2.4-三烯 -3-基 -3-甲基 -5-氧代 -1.5-二氢吡唑 -4-亚基) - 肼基 1-2'-羟基联苯基 -3-羧酸 3'-Γ '-Π-bicyclic "4.2.01 辛垸-1ί6), 2.4-trien-3-yl-3-methyl-5-oxo-1.5-dihydropyrazole-4-ylidene) - Mercapto 1-2'-hydroxybiphenyl-3-carboxylic acid
3-溴 -双环 [4.2.0]辛垸 -1(6),2,4-三烯 3-bromo-bicyclo [4.2.0] octone -1(6), 2,4-triene
室温下，将双环 [4.2.0]辛垸 -1(6),2,4-三烯 5a(7.9 g, 76 mmol)溶解于 80 mL水中， 冰浴冷却后缓慢滴加 3.9 mL溴， 加毕撤去冰浴， 反应混合物缓慢升至室温后搅拌 过夜。 TLC监测反应至原料反应完全， 停止反应。 向反应液中加入 50 mL正已烷 Na2S03(3 g， 23.8 mmol), 加毕于室温下搅拌 30分钟。 反应混合物分液后取有 机层用无水硫酸钠干燥， 过滤除去干燥剂， 有机相减压浓缩得到标题产物 3-溴-双 环 [4.2.0]辛垸 -1(6),2，4-三烯 5b(13.53 g， 无色油状液体)， 直接投入下步反应。 Dicyclo[4.2.0]octyl-1(6), 2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature, and 3.9 mL of bromine was slowly added dropwise after cooling in an ice bath. The ice bath was removed and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC until the starting material was completely reacted and the reaction was stopped. 50 mL of n-hexane Na 2 S0 3 (3 g, 23.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was separated, the organic layer was dried (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Triene 5b (13.53 g, colorless oily liquid) was directly introduced into the next step.
MS m/z (ESI): 181.8[M-1]
第二歩 MS m/z (ESI): 181.8 [M-1] Second
(N-双环 [4.2.0]辛垸 -1(6)，2,4-三烯 -3-基 -Ν'-叔丁氧羰基-肼基) -碳酸叔丁酯 将 3-溴-双环 [4.2.0]辛垸 -1(6),2,4-三烯 5b(13.5 g， 73.8 mmol)溶解于 100 mL四 氢呋喃 (千燥)中， 用干冰-乙醇浴冷却至 -78°C后加入正丁基锂 (66 mL， 165 mmol), 加毕继续低温搅拌。 将偶氮二甲酸二叔丁酯 (20.1 g， 87.4 mmol)溶解于 80 mL四氢 呋喃 (千燥)中， 缓慢加入到上述反应液中， 加毕撤去干冰-乙醇浴， 反应体系温度 缓慢升至室温后搅拌过夜。 TLC 监测原料反应完全后停止反应。 向反应体系中加 入 100 mL水淬灭反应， 反应液分液， 水相用乙酸乙酯萃取 (100 mLx2)， 合并有机 相，有机相用饱和氯化钠溶液洗涤 (150 mLx l),无水硫酸钠干燥，过滤除去干燥剂， 滤液经柱层析得到标题产物 (N-双环 [4.2.0]辛烷 -1(6),2,4-三烯 -3-基 -Ν'-叔丁氧羰基- 肼基) -碳酸叔丁酯 5c(4.07 g， 黄色油状液体)， 产率： 16.5 %。 第三步 (N-bicyclo[4.2.0]octyl-1(6),2,4-trien-3-yl-indole-tert-butoxycarbonyl-indenyl)-tert-butyl carbonate, 3-bromo-bicyclic [4.2.0] Xinzhi-1(6), 2,4-triene 5b (13.5 g, 73.8 mmol) was dissolved in 100 mL of tetrahydrofuran (dry) and cooled to -78 °C with a dry ice-ethanol bath. Add n-butyllithium (66 mL, 165 mmol) and continue to stir at low temperature. Di-tert-butyl azodicarboxylate (20.1 g, 87.4 mmol) was dissolved in 80 mL of tetrahydrofuran (dry), slowly added to the above reaction solution, and the dry ice-ethanol bath was removed, and the temperature of the reaction system was slowly raised to room temperature. Stir overnight. The TLC monitors the reaction of the starting material and stops the reaction. The reaction mixture was quenched by the addition of 100 mL of water, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phase was combined and the organic phase was washed with saturated sodium chloride solution (150 mL×l) Dry over sodium sulfate, filter to remove the desiccant, and filtrate to give the title product (N-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-indole-tert-butyl Oxycarbonyl-indenyl)-tert-butyl carbonate 5c (4.07 g, yellow oily liquid), Yield: 16.5%. third step
2-双环 [4.2.0]辛垸 -1(6),2,4-三烯- 3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 将 (N-双环 [4.2.0]辛烷 -1(6),2,4-三烯 -3-基- Ν'-叔丁氧羰基-肼基) -碳酸叔丁酯 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one (N-bicyclo[ 4.2.0] Octane-1(6),2,4-trien-3-yl-Ν'-tert-butoxycarbonyl-indenyl)-tert-butyl carbonate
5c(4.0 g， 12 mmol)溶解于 30 mL乙酸中， 加入 30 mL三氟乙酸， 室温搅拌 30分 钟， 向反应体系中加入 3-氧代-丁酸甲酯 (1.6 mL， 15 mmol)于 100Ό油浴中搅拌 1.5 小时， TLC表明原料反应完全，停止反应。反应液减压蒸除溶剂，分批加入 100 mL 水， 60 mL 乙酸乙酯和碳酸钠 (3 g)， 加毕反应液分液， 水相用乙酸乙酯萃取 (40 mLx2),合并有机相，有机相用饱和氯化钠溶液洗涤 (lOO mLx l),无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产物 2-双环 [4.2.0]辛垸 -1(6),2,4- 三烯 -3-基 -5-甲基- 2,4-二氢吡唑 -3-酮 5d(910 mg， 黄色固体)， 产率： 37.9%。 5c (4.0 g, 12 mmol) was dissolved in 30 mL of acetic acid, 30 mL of trifluoroacetic acid was added, and stirred at room temperature for 30 minutes. To the reaction system was added methyl 3-oxo-butyrate (1.6 mL, 15 mmol) at 100 Torr. After stirring for 1.5 hours in an oil bath, TLC showed that the starting material was completely reacted and the reaction was stopped. The reaction solution was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc) The organic phase was washed with a saturated sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate, and filtered and evaporated to remove the solvent, and the filtrate was concentrated under reduced pressure to give the title product 2-bis[[. (6), 2,4-Trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one 5d (910 mg, yellow solid), Yield: 37.9%.
MS m/z (ESI): 201.2[M+ 1] 第四步 MS m/z (ESI): 201.2 [M+ 1] Step 4
3'-[Ν'-(1-双环 [4.2.0]辛垸 -1(6),2,4-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) - 肼基] -2'-羟基联苯基 -3-羧酸 3'-[Ν'-(1-bicyclo[4.2.0]octyl-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-di Hydropyrazol-4-ylidene)-indenyl]-2'-hydroxybiphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸 If (258 mg, 0.83 mmol)溶解于 10 mL盐 酸 (IN)中， 滴加入 10 mL亚硝酸钠溶液 (63 mg, 0.92 mmol), 再加入 2-双环 [4.2.0] 辛垸 -1(6),2,4-三烯 -3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 5d (150 mg, 0.75 mmol), 用饱和 碳酸氢钠溶液将反应液 pH调至 8, 加入 10 mL乙醇， 升至室温搅拌过夜。 TLC跟 踪至原料消失， 过滤。 所得固体溶于 30 mL水中， 用浓盐酸调节 pH至 3-4左右， 继续过滤所得固体用二氯甲烷洗涤 (8 mL) , 干燥后得到标题产物 3'-[Ν'-(1-双环 [4.2.0]辛烷 -1(6),2,4-三烯 -3-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 ]-2'-羟基联 苯基 -3-羧酸 5(198 mg， 红色固体)， 产率： 60 %。 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid If (258 mg, 0.83 mmol) was dissolved in 10 mL of hydrochloric acid (IN) under ice bath, and 10 mL of sodium nitrite solution (63 mg) was added dropwise. , 0.92 mmol), followed by 2-bicyclo[4.2.0] octone-1(6), 2,4-trien-3-yl-5-methyl-2,4-dihydropyrazole-3- Ketone 5d (150 mg, 0.75 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 10 mL of ethanol was added, and the mixture was stirred at room temperature overnight. The TLC traces to the disappearance of the material and is filtered. The obtained solid was dissolved in 30 mL of water, and the pH was adjusted to about 3-4 with concentrated hydrochloric acid. The obtained solid was filtered and washed with dichloromethane (8 mL), and dried to give the title product 3'-[Ν'-(1-bicyclo[ 4.2.0] Octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-2'-Hydroxybiphenyl-3-carboxylic acid 5 (198 mg, red solid), Yield: 60%.
MS m/z (ESI )： 439.5[M-1]
'H MR(400MHz, DMSO /6): δ 2.33(s, 3H), 3.16(m, 4H), 7.14(m, 3H), 7.64(m, 2H); 7.79(m, 2H), 7.80(m, 1H), 7.98(m, 1H), 8.18(s, 1H), 9.61(s, 1H), 12.93(br, 1H), 13.75(br, 1H) 实施例 6 MS m/z (ESI): 439.5 [M-1] 'H MR (400MHz, DMSO /6): δ 2.33(s, 3H), 3.16(m, 4H), 7.14(m, 3H), 7.64(m, 2H) ; 7.79(m, 2H), 7.80(m , 1H), 7.98 (m, 1H), 8.18 (s, 1H), 9.61 (s, 1H), 12.93 (br, 1H), 13.75 (br, 1H) Example 6
5-(2-羟基 -3-ίΝ'-「3-甲基 -5-氧代 -l-(5.6.7.8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚 基 1-肼基 苯) -1 ,2,4-三甲基 -1H-吡咯 -3-羧酸乙酉 I
第一步 5-(2-hydroxy-3-ίΝ'-"3-methyl-5-oxo-l-(5.6.7.8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole -4-indolyl 1-mercaptophenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid acetamidine I first step
2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1 ,3,2]硼酸乙二醇酯 将 1-溴 -2-甲氧基 -3-硝基苯 lc (67 g, 0.289 mol)、 4,4,4',4，,5,5,5，,5，-八甲基 -2,2'- 联 -1,3,2-硼酸乙二醇酯（110 g, 0.433 mol)、四 (三苯基膦)钯 (11.80 g, 14.44 mmol)和乙 酸钾 (71 g, 0.724 mol)溶解于 600 mL 乙二酸二甲醚中， 加热回流 17小时。 TLC跟 踪至原料消失， 减压浓缩， 用硅胶柱层析分离纯化， 得到标题产物 2-(2-甲氧基 -3- 硝基苯基) -4，4,5,5-四甲基 -[1 ,3,2]硼酸乙二醇酯 6a(50.5 g, 黄色晶体)。产率： 61.9%。 1-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1 ,3,2]boronic acid ethylene glycol ester 1-bromo-2-methoxy 3-nitrobenzene lc (67 g, 0.289 mol), 4,4,4',4,5,5,5,5,-octamethyl-2,2'-linked-1,3 , 2-Butyl borate (110 g, 0.433 mol), tetrakis(triphenylphosphine)palladium (11.80 g, 14.44 mmol) and potassium acetate (71 g, 0.724 mol) dissolved in 600 mL of dimethyl dimethylate In the ether, the mixture was heated under reflux for 17 hours. TLC was traced to the disappearance of the starting material, which was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2-methoxy-3-nitrophenyl) -4,4,5,5-tetramethyl- [1,3,2]Ethyl borate 6a (50.5 g, yellow crystals). Yield: 61.9%.
第二步 Second step
3,5-二甲基 -1H-吡咯 -2,4-二羧酸 4-乙酯 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester
冰浴下， 将 3,5-二甲基 -1H-吡咯 -2,4-二羧酸 2-叔丁酯 4-乙酯 6b(5.34 g， 20 mmol)溶解于三氟醋酸中 (7.4 mL， 100 mmol), 搅拌 2小时， TLC监测反应至原料 反应完全， 向反应液中加入 40 mL水， 过滤， 滤饼用二氯甲烷洗涤后干燥， 得到
标题产物 3,5-二甲基 -1 H-吡咯 -2,4-二羧酸 4-乙酯 6c(3.65 g， 粉色固体)， 产率： 86.5%。 3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 6b (5.34 g, 20 mmol) was dissolved in trifluoroacetic acid (7.4 mL). , 100 mmol), stirred for 2 hours, TLC was monitored until the reaction of the starting material was completed. 40 mL of water was added to the reaction mixture, and the mixture was filtered, washed with dichloromethane and dried. The title product, 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, pink solid), yield: 86.5%.
MS m/z (ESI): 209.8[M-1] 第三步 MS m/z (ESI): 209.8[M-1] Step 3
5-碘 -2,4-二甲基 -1H-吡咯 -3-羧酸乙酯 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester
将 3,5-二甲基 -1 H-吡咯 -2,4-二羧酸 4-乙酯 6c(3.65 g, 17.3 mmol)加入到 l OO mL 二氯甲垸和 10 mL水的混合溶剂中，再加入碘化钾 (11.5 g， 69.2 mmol)和碘 (4.39 g， 17.3 mmol), 加毕加热回流 2小时， TLC监测反应至原料反应完全， 反应液冷却至 室温， 加入 20 mL水和 lO mL硫代硫酸钠溶液 (2M；)， 用二氯甲垸萃取 (30 mL <3)， 合并有机相， 有机相用饱和食盐水洗涤， 无水硫酸镁干燥， 过滤除去干燥剂， 滤 液减压浓缩得到标题产物 5-碘 -2,4-二甲基 -1H-吡咯 -3-羧酸乙酯 6d(4.1 g, 橙色固 体）， 产率： 80.8%。 第四歩 Add 3,5-dimethyl-1 H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, 17.3 mmol) to a mixed solvent of 100 mL of dichloromethane and 10 mL of water. Further, potassium iodide (11.5 g, 69.2 mmol) and iodine (4.39 g, 17.3 mmol) were added, and the mixture was heated under reflux for 2 hours. The reaction was monitored by TLC until the reaction was completed. The reaction mixture was cooled to room temperature, and 20 mL of water and 10 mL of sulfur were added. The sodium sulphate solution (2M;) was extracted with chloroformic acid (30 mL <3). The organic phase was combined and washed with brine, dried over anhydrous magnesium sulfate. The title product ethyl 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylate 6d (4.1 g, orange solid). Fourth
5-碘 -1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 . Ethyl 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylate .
将 5-碘 -2,4-二甲基 -1H-吡咯 -3-羧酸乙酯 6d(4.1 g, 13.99 mmol)溶解于 80 mL四 氢呋喃中， 加入 4-甲基苯磺酸甲酯 (2.73 g， 14.69 mmol)和叔丁醇钠 (2.02 g， 20.99 mmol), 加毕室温搅拌 0.5小时， TLC监测反应至原料反应完全， 反应液过滤， 滤 饼用四氢呋喃洗涤， 滤液减压浓缩， 得到标题产物 5-碘 -1,2,4-三甲基 -1H-吡咯 -3- 羧酸乙酯 6e(3.8 g, 灰色固体)， 产率： 88.6%。 Ethyl 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylate 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl 4-methylbenzenesulfonate (2.73) was added. g, 14.69 mmol) and sodium tert-butoxide (2.02 g, 20.99 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was filtered, and the filter cake was washed with THF. The product 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, m.p.).
MS m/z (ESI): 308.1 [M+1] MS m/z (ESI): 308.1 [M+1]
'HNMR(400MHz, CDC13): δ 4.287〜4.340(q, 2H), 3.561(s, 3H), 2.618(s, 3H), 2.888(s, 3H), 1.369-1.405(t, 3H) 第五步 'HNMR (400MHz, CDC1 3 ): δ 4.287~4.340(q, 2H), 3.561(s, 3H), 2.618(s, 3H), 2.888(s, 3H), 1.369-1.405(t, 3H) step
5-(3-硝基 -2-甲氧基 -苯基 )-1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 将 5-碘 -1,2,4-三甲基 -1 H-吡咯 -3-羧酸乙酯 6e(2.88 g， 9.38 mmol)溶解于 25 mLl ,4-二氧六环中， 加入 2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1,3,2]硼酸乙二 醇酉旨 6a (3.6 g， 10.3 mmol) 四 (三苯基膦)钯 (270 mg， 0.234 mmol),碳酸钠（1.99 g， 18.77 mmol)和 10 mL水， 加毕加热回流 3小时， TLC监测反应至原料反应完全， 反应液冷却至室温， 加入 30 mL水， 用乙酸乙酯萃取 (30 ηΛχ3)， 合并有机相， 有 机相用饱和食盐水洗涤， 无水硫酸镁干燥， 过滤除去干燥剂， 滤液减压浓缩得到 标题产物 5-(3-硝基 -2-甲氧基 -苯基 )-1，2,4-三甲基 -1Η-吡咯 -3-羧酸乙酯 6f(1.25 g，黄 色油状液体)， 产率： 40.4%。 Ethyl 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 5-iodo-1,2,4-tri Ethyl methyl-1 H-pyrrole-3-carboxylate 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 4-dioxane, and 2-(2-methoxy-3-nitrobenzene was added. -4,4,5,5-tetramethyl-[1,3,2]boronic acid ethylene glycol hydrazine 6a (3.6 g, 10.3 mmol) tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol) ), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water, heated and refluxed for 3 hours, the reaction was monitored by TLC until the reaction of the starting material was completed, the reaction mixture was cooled to room temperature, 30 mL of water was added, and extracted with ethyl acetate (30 η Λχ 3 The organic phase was combined, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate. 1,2,4-Trimethyl-1Η-pyrrole-3-carboxylic acid ethyl ester 6f (1.25 g, yellow oily liquid), Yield: 40.4%.
MS m/z (ESI): 333.2[M+1] MS m/z (ESI): 333.2 [M+1]
'H MR(400MHz, CDC13): δ 7.817-7.84 l(m, 1H), 7.457~7.476(m, 1H),
7.284〜7.324(m, 1H), 4.322~4.375(q, 2H), 3.521 (s, 3H), 3.316(s, 3H), 2.625(s, 3H); 2.177(s, 3H), 1.398-1.434(t, 3H) 第六歩 'H MR(400MHz, CDC1 3 ): δ 7.817-7.84 l(m, 1H), 7.457~7.476(m, 1H), 7.284~7.324(m, 1H), 4.322~4.375(q, 2H), 3.521 (s, 3H), 3.316(s, 3H), 2.625(s, 3H) ; 2.177(s, 3H), 1.398-1.434( t, 3H) sixth
5-(3-氨基 -2-甲氧基 -苯基 )-1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 将 5- (3-硝基 -2-甲氧基 -苯基 )-1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 6f(300 mg， 0.9 mmol)溶解于 5 mL乙酸乙酯中， 加入甲酰胺 (227 mg， 1.61 mmol)和 60 mg钯 /碳， 加热回流 1 小时， TLC监测反应至原料反应完全， 反应液过滤， 滤饼用乙酸乙酯 洗涤， 滤液减压浓缩得到标题产物 5-(3-氨基 -2-甲氧基 -苯基 )-1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 6g(234 mg， 白色固体)， 产率： 86%。 Ethyl 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 5-(3-nitro-2-methoxy Ethyl-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (300 mg, 0.9 mmol) was dissolved in ethyl acetate (5 mL). 1.61 mmol) and 60 mg of palladium on carbon were heated under reflux for 1 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate. -Methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 g (234 mg, white solid), yield: 86%.
MS m/z (ESI): 303.4[M+1] MS m/z (ESI): 303.4 [M+1]
'HNMR(400MHz, CDC13): δ 6.968~7.006(m, 1Η), 6.817~6.840(m, 1H), 'HNMR (400MHz, CDC1 3 ): δ 6.968~7.006(m, 1Η), 6.817~6.840(m, 1H),
6.595〜6.618(m, 1H)， 4.31卜 4.364(q, 2H), 3.381(s, 3H), 3.315(s, 3H)， 2.615(s, 3H), 2.181(s, 3H), 1.391~1.426(t, 3H) 第七歩 6.595~6.618(m, 1H), 4.31b 4.364(q, 2H), 3.381(s, 3H), 3.315(s, 3H), 2.615(s, 3H), 2.181(s, 3H), 1.391~1.426( t, 3H) seventh
5-(3-氨基 -2-羟基苯基) -1,2，4-三甲基 -】H-吡咯 -3-羧酸乙酯氢溴酸盐 将 5-(3-氨基- 2-甲氧基 -苯基 )- 1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 6g(210 mg， 0.69 mmol)溶解于 5 mL二氯甲垸中， 加入溴化硼（1.39 mL, 2.78 mmol), 室温反应 0.5 小时， TLC 监测反应至原料反应完全， 用甲醇淬灭反应， 反应液减压浓缩后加入 50 mL乙酸乙酯和 15 mL饱和碳酸氢钠溶液， 搅拌均匀后分液， 有机相用饱和食 盐水洗涤， 无水硫酸镁干燥，'过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题 产物 5-(3-氨基 -2-羟基苯基)- 1,2，4-三甲基 -1H-吡咯- 3-羧酸乙酯氢溴酸盐 6h(165 mg， 白色固体)， 产率： 82.5%。 5-(3-Amino-2-hydroxyphenyl)-1,2,4-trimethyl-]H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 5-(3-amino-2-methyl Ethyloxy-phenyl)- 1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 g (210 mg, 0.69 mmol) dissolved in 5 mL of dichloromethane, boron bromide (1.39 mL, 2.78 mmol), react at room temperature for 0.5 h. The reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with methanol. The reaction mixture was concentrated under reduced pressure. 50 mL of ethyl acetate and 15 mL of saturated sodium bicarbonate were added and stirred. After the liquid separation, the organic phase was washed with brine, dried over anhydrous magnesium sulfate 2,4-Trimethyl-1H-pyrrole-3-carboxylate ethyl ester hydrobromide 6h (165 mg, white solid), yield: 82.5%.
MS m/z (ESI): 289.3[M+1] MS m/z (ESI): 289.3 [M+1]
'HNMR(400MHz, DMSO-t d): δ 7.313~7.396(m, 1H), 7.098-7.117(m, 1H), 'HNMR (400MHz, DMSO-t d): δ 7.313~7.396(m, 1H), 7.098-7.117(m, 1H),
6.993〜7.032(m， 1H)， 4.173~4.227(q, 2H), 3.221(s, 3H), 1.979(s, 3H), 1.242-1.295(t, 3H) 第八步 6.993~7.032(m, 1H), 4.173~4.227(q, 2H), 3.221(s, 3H), 1.979(s, 3H), 1.242-1.295(t, 3H) Step 8
5-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1- (5,6,7,8-四氢萘亚甲基 -2-基)- 1,5-二氢吡唑 -4-亚 基] -肼基 苯 )-1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯 冰浴下将 5-(3-氨基 -2-羟基苯基) -1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯氢溴酸盐 6h (140 mg， 0.51 mmol)溶解于 1.76 mL盐酸 (IN)中，滴加入 1 mL亚硝酸钠溶液 (39 mg， 0.56 mmol), 搅拌 20分钟， 再加入 5-甲基 -2-(5,6,7，8-四氢萘 -2-基) -2,4-二氢吡唑 -3- 酮 3i (105 mg, 0.46 mmol), 用饱和碳酸氢钠溶液将反应液. pH调至 8， 加入 1 mL 乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过滤， 滤饼干燥后用二氯甲垸溶解，
用饱和食盐水洗涤， 有机相减压浓缩后柱层析， 得到标题产物 5-(2-羟基 -3-{N'-[3- 甲基 -5-氧代 -1-(5,6,7,8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚基] -肼基 苯) -1 ,2,4- 三甲基 -1H-吡咯 -3-羧酸乙酯 6(120 mg， 红色固体 )。 产率： 50.8%。 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5 -dihydropyrazole-4-ylidene]-mercaptophenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 5-(3-amino-2-) Hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6h (140 mg, 0.51 mmol) dissolved in 1.76 mL of hydrochloric acid (IN), added dropwise 1 mL sodium nitrite solution (39 mg, 0.56 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazole-3-one 3i (105 mg, 0.46 mmol), the reaction mixture was adjusted to pH 8 with a saturated sodium hydrogen carbonate solution, and 1 liter of ethanol was added and allowed to warm to room temperature overnight. TLC traces to the disappearance of the raw materials, filtration, and the filter cake is dried and dissolved with methylene chloride. The organic phase was concentrated under reduced pressure and then purified tolululululululululululululululululululululu 7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ylidene]-mercaptophenyl)-1,2,4-trimethyl-1H-pyrrole- Ethyl 3-carboxylate 6 (120 mg, red solid). Yield: 50.8%.
MS m/z (ESI): 514.1 [M+1] MS m/z (ESI): 514.1 [M+1]
'HNMR(400MHz, DMSO-C 6): 51.84(m,4H), 2.14(s,3H), 2.41(s,3H), 2.57(s,3H), 2.80(m,4H), 3.34(s,3H), 3.87(s,3H), 6.51(m,lH), 7.00(d,J=7.6Hz,l H), 7.11(m,2H), 7.71(m,2H), 13.82(br,lH) 实施例 7 'HNMR (400MHz, DMSO-C 6): 51.84 (m, 4H), 2.14 (s, 3H), 2.41 (s, 3H), 2.57 (s, 3H), 2.80 (m, 4H), 3.34 (s, 3H), 3.87(s,3H), 6.51(m,lH), 7.00(d,J=7.6Hz,l H), 7.11(m,2H), 7.71(m,2H), 13.82(br,lH) Example 7
3'-{Ν'-Π-(2.3-二氢苯并呋喃 - 5-基) -3-甲基- 5-氧代 -1,5-二氢吡唑 -4-亚基卜肼基 2'-羟 3'-{Ν'-Π-(2.3-Dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 2'- Hydroxyl
7a 7b 7c 第一步 7a 7b 7c First step
1- (2,3-二氢苯并呋喃基)肼基 -1,2-二羧酸二 (2,2,2-三氯乙酯） 将 2，3-二氢苯并呋喃 7a (0.6 mL, 5.32 mmol), 二 (2,2,2-三氯乙基)偶氮二碳酸酯 (1.96 g, 5.15 mmol)和氯化锌 (920 mg, 6.76 mmol)溶解于 40 mL二氯甲烷中，室温反 应过夜。 TLC跟踪至原料消失， 用硅胶柱层析分离纯化， 得到标题产物 1-(2,3-二 氢苯并呋喃基)肼基 -1,2-二羧酸二 (2,2,2-三氯乙酯) 7b(2.5 g， 白色固体）。 产率： 96.6%。 第二步 1-(2,3-Dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester) 2,3-dihydrobenzofuran 7a (0.6 mL, 5.32 mmol), bis(2,2,2-trichloroethyl)azodicarbonate (1.96 g, 5.15 mmol) and zinc chloride (920 mg, 6.76 mmol) dissolved in 40 mL of dichloromethane Reactive overnight at room temperature. TLC was traced to disappearance of the starting material, and purified by silica gel column chromatography to give the title product 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2- Chloroethyl ester) 7b (2.5 g, white solid). Yield: 96.6%. Second step
2- (2,3-二氢苯并呋喃 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 将 】-(2,3-二氢苯并呋喃基)肼基 -1 ,2-二羧酸 二 (2,2,2-三氯乙酯) 7b (2.9 g, 5.8 mmol)溶解于 50 mL乙醇和 5 mL甲醇的混合溶剂中，再加入锌粉 (10.8 g, 166 mmol) 和乙酸铵溶液 (15 mL, 1 mol/L)室温反应 1小时， 滴加乙酰乙酸乙酯 (0.75 mL, 5.9 mmol), 加热回流 2小时。 TLC跟踪至原料消失， 将反应液冷却至室温， 过滤， 滤 液减压浓缩后用硅胶柱色谱法纯化， 得到标题产物 2-(2,3-二氢苯并呋喃 -5-基) -5-
2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one]-(2,3-dihydrobenzofuranyl) Hydrazin-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester) 7b (2.9 g, 5.8 mmol) was dissolved in a mixed solvent of 50 mL of ethanol and 5 mL of methanol, followed by zinc powder ( 10.8 g, 166 mmol) and ammonium acetate solution (15 mL, 1 mol/L) were reacted at room temperature for 1 hour, ethyl acetoacetate (0.75 mL, 5.9 mmol) was added dropwise, and the mixture was refluxed for 2 hr. TLC was traced to the disappearance of the starting material, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2,3-dihydrobenzofuran-5-yl) -5-
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氩气氛下将 3-溴-苯甲腈 8a(18.2 g, 0.1 mol)和氯化按 (5.9 g, 0.11 mol)溶解于 80 mLN,N'-二甲基甲酰胺中， 再加入叠氮化钠 (7.16 g, 0.11 mol)， 加热至 100°C反应过 夜。 冷却至 60°C， 减压浓缩除去 Ν,Ν'-二甲基甲酰胺， 加入 100 mL水和 4 mL浓 盐酸， 搅拌 1小时， 过滤， 干燥， 得到标题产物 5-(3-溴-苯基) -1H-四唑 8b(23 g， 白色固体)。 第二歩 100000/600ZN3/X3d Dissolve 3-bromo-benzonitrile 8a (18.2 g, 0.1 mol) and chlorination (5.9 g, 0.11 mol) in 80 mL of N,N'-dimethylformamide under argon atmosphere, then add azide Sodium (7.16 g, 0.11 mol) was heated to 100 ° C overnight. The mixture was cooled to 60 ° C, and concentrated under reduced pressure to remove hydrazine, <RTI ID=0.0>> Base) -1H-tetrazole 8b (23 g, white solid). Second
5-(2'-甲氧基-联苯基 -3-基) -1H-四唑 5-(2'-methoxy-biphenyl-3-yl)-1H-tetrazole
氩气氛下将 5-(3-溴-苯基) -1 H-四唑 8b(20 g, 89 mmol)和邻甲氧基苯硼酸 (14.2 g, 93.3 mmol)溶解于 530 mL 1，4-二氧六环中， 加入四 (三苯基膦)钯 (1.84 g)和碳酸钠 (18.9 g, 178 mmol) , 加热回流过夜。 TLC跟踪至原料消失， 减压浓缩除去 1，4-二氧 六环， 加入盐酸 (200 mL, 6 mol/L)， 冷却 2小时， 弃去水层， 残余物溶解于 500 mL 乙酸乙酯中，用 250 mL水洗涤，无水硫酸钠干燥，减压浓缩，残余物溶解于 25 mL 乙酸乙酯中， 静置过夜， 过滤， 得到标题产物 5-(2'-甲氧基-联苯基 -3-基) -1 H-四唑 8c(15 g， 淡黄色固体）。 产率： 68.2%。 第三步 5-(3-Bromo-phenyl)-1H-tetrazole 8b (20 g, 89 mmol) and o-methoxyphenylboronic acid (14.2 g, 93.3 mmol) were dissolved in 530 mL 1,4- argon. To the dioxane, tetrakis(triphenylphosphine)palladium (1.84 g) and sodium carbonate (18.9 g, 178 mmol) were added, and the mixture was heated to reflux overnight. The TLC was traced to disappearance of the starting material. The 1,4-dioxane was concentrated under reduced pressure. Hydrochloric acid (200 mL, 6 mol/L) was added, and the mixture was cooled for 2 hours, the aqueous layer was discarded, and the residue was dissolved in 500 mL of ethyl acetate. Was washed with 250 mL of water, dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjjjjjjj -3-yl)-1H-tetrazole 8c (15 g, pale yellow solid). Yield: 68.2%. third step
3'-(1 H-四唑 -5-基) -联苯基 -2-醇 3'-(1 H-tetrazol-5-yl)-biphenyl-2-ol
氩气氛下将 5-(2'-甲氧基-联苯基 -3-基;) -1 H-四唑 8c(15.5 g, 61.5 mol)溶解于 195 mL 乙酸中， 加入 195 mL氢溴酸， 加热回流 5小时。 TLC跟踪至原料消失， 冷却 过夜， 过滤， 固体溶解于 500 mL乙酸乙酯中， 用水洗涤 (500 tnLx2), 无水硫酸钠 干燥， 过滤， 减压浓缩， 加入 100 mL乙酸乙酯重结晶， 得到标题产物 3'-(1 Η-四唑 -5-基)-联苯基 -2-醇 8d(12 g， 白色固体)。 产率： 82.8%。 第四步 5-(2'-Methoxy-biphenyl-3-yl;)-1H-tetrazole 8c (15.5 g, 61.5 mol) was dissolved in 195 mL of acetic acid under argon atmosphere, and 195 mL of hydrobromic acid was added. , heating under reflux for 5 hours. TLC was traced to the disappearance of the starting material, and the mixture was filtered, and the solid was dissolved in ethyl acetate (500 mL), washed with water (500 tnLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title product 3'-(1 Η-tetrazol-5-yl)-biphenyl-2-ol 8d (12 g, white solid). Yield: 82.8%. the fourth step
3-硝基 -3'-(1Η-四唑 -5-基) -联苯基 -2-醇 3-nitro-3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol
氩气氛下将 3'-(1Η-四唑 -5-基) -联苯基 -2-醇 8d(3.5 g, 14.7 mmol)溶解于 145mL 乙醇中， 35 °C下滴加发烟硝酸 (0.565 mL， 13.2 mmol), 室温反应 1小时， 加入 150 mL水， 静置过夜， 过滤， 固体用 100 mL水洗涤， 溶解于 500 mL乙酸乙酯和 250 mL水中， 萃取， 有机相用饱和氯化钠溶液洗涤， 无水硫酸镁干燥， 用硅胶柱层析 分离纯化，得到标题产物 3-硝基 -3'-(1Η-四唑 -5-基) -联苯基 -2-醇 8e(l g，黄色固体)。 产率： 27.0%。 3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol 8d (3.5 g, 14.7 mmol) was dissolved in 145 mL of ethanol under argon atmosphere, and fuming nitric acid (0.565) was added dropwise at 35 °C. mL, 13.2 mmol), react at room temperature for 1 hour, add 150 mL of water, let stand overnight, filter, solid wash with 100 mL water, dissolve in 500 mL of ethyl acetate and 250 mL water, extract, organic phase with saturated sodium chloride The solution was washed with MgSO.sub.sub.sub.sub.subsubsubsubsubsubsubsubsubsubsubsubsub Yellow solid). Yield: 27.0%.
MS m/z (ESI): 282[M-1] 第五步 MS m/z (ESI): 282[M-1] Step 5
3-氨基 -3'-(1Η-四唑- 5-基)-联苯基 -2-醇 盐酸盐 将 3-硝基 -3'-(1Η-四唑 -5-基) -联苯基 -2-醇 8e (2.5 g, 8.83 mmol)溶解于 118 mL乙
醇和 78.6 mL水中， 再加入氢氧化钠溶液 (2.95 mL, 3 mol/L)和 313 mg钯 -碳， 于氢 化仪中在 3个大气压下用氢气氢化， 室温反应 3小时。 TLC跟踪至原料消失， 过 滤， 滤液中加入盐酸 (60 mL, 3 mol/L)， 减压浓缩， 向残余物中加入少量水， 过滤， 固体用少量水和正己垸洗涤， 干燥， 得到标题产物 3-氨基 -3'-(1Η-四唑 -5-基:) -联苯 基 -2-醇盐酸盐 8f(2.33 g， 红棕色固体；)。 3-amino-3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 3-nitro-3'-(1Η-tetrazol-5-yl)-biphenyl Base-2-ol 8e (2.5 g, 8.83 mmol) dissolved in 118 mL B Alcohol and 78.6 mL of water were further added with sodium hydroxide solution (2.95 mL, 3 mol/L) and 313 mg of palladium-carbon, hydrogenated in hydrogenation at 3 atm. in a hydrogenation apparatus, and reacted at room temperature for 3 hours. After the TLC was traced to the disappearance of the starting material, the filtrate was filtered, and hydrochloric acid (60 mL, 3 mol/L) was added to the filtrate, and concentrated under reduced pressure. A small amount of water was added to the residue, filtered, and the solid was washed with a small amount of water and hexane and dried to give the title product. 3-Amino-3'-(1Η-tetrazol-5-yl:)-biphenyl-2-ol hydrochloride 8f (2.33 g, red-brown solid;
MS m/z (ESI): 252[M+1] 第六步 MS m/z (ESI): 252[M+1] Step 6
1- (3,3-二甲基茚满 -5-基)肼基 -1，2-二羧酸 二 (叔丁酯） 将 6-溴 -1,1-二甲基茚满 (WO2005066115) 8g (4.32 g, 19.27 mmol)溶解于 40mL 四氢呋喃中， -78°C下滴加丁基锂（15.67 mL, 1.6mol/L, 25.05 mmol), 反应 40分钟， 加入偶氮二甲酸二叔丁酯 (5.32 g, 23.12 mmol)的 30 mL四氢呋喃溶液， -78°C下继 续反应 3小时。 TLC跟踪至原料消失， 加入 5mL甲醇， 反应液升至室温， 用硅胶 过滤，滤液减压浓缩，用硅胶柱层析分离纯化，得到标题产物 1-(3,3-二甲基茚满 -5- 基)肼基 -] ,2-二羧酸 二 (叔丁酯) 8h(2.70 g， 黄色固体)。 产率： 37.2%。 第七步 1-(3,3-Dimethylindan-5-yl)indolyl-1,2-dicarboxylic acid di(tert-butyl ester) 6-bromo-1,1-dimethylindole (WO2005066115) 8 g (4.32 g, 19.27 mmol) was dissolved in 40 mL of tetrahydrofuran, and butyl lithium (15.67 mL, 1.6 mol/L, 25.05 mmol) was added dropwise at -78 ° C for 40 minutes, and di-tert-butyl azodicarboxylate was added. (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran solution, the reaction was continued at -78 °C for 3 hours. The title product (1-(3,3-dimethylindane-5) was obtained by chromatography. - yl) fluorenyl-], 2-dicarboxylic acid bis(tert-butyl ester) 8h (2.70 g, yellow solid). Yield: 37.2%. Seventh step
2- (3,3-二甲基茚满- 5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 将 1-(3,3-二甲基茚满 -5-基)肼基 -1,2-二羧酸 二 (叔丁酯 )8h (2.70 g, 7.18 mmol) 溶解于 lOOmL乙酸中， 加入 20 mL三氟乙酸， 室温反应 2小时， 加入乙酰乙酸乙 酯 (0.98 g, 7.54 mmol), 加热至 100Ό反应 2小时。 TLC跟踪至原料消失， 冷却至室 温， 减压浓缩除去乙酸， 用饱和碳酸氢钠溶液中和反应液中的酸， 用乙酸乙酯萃 取， 合并有机相， 用饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 2-(3,3-二甲基茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 8i 1.0 g， 淡褐色固体；)。 产率： 47.7%。 2-(3,3-Dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 1-(3,3-dimethylindan-5 -yl) decyl-1,2-dicarboxylic acid di(tert-butyl ester) 8h (2.70 g, 7.18 mmol) dissolved in 100 mL of acetic acid, added with 20 mL of trifluoroacetic acid, reacted at room temperature for 2 hours, added ethyl acetoacetate (0.98 g, 7.54 mmol), heated to 100 Torr for 2 hours. The TLC was traced to the disappearance of the starting material, cooled to room temperature, and concentrated under reduced pressure to remove acetic acid. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic phase was combined and washed with saturated sodium chloride solution. The residue was dried over EtOAcjjjjjjjjjjjjj Dihydropyrazol-3-one 8i 1.0 g, light brown solid;). Yield: 47.7%.
MS m/z (ESI): 243 [M+l] 第八步 MS m/z (ESI): 243 [M+l] Step 8
2-(3,3-二甲基茚满 -5-基) -4-{[2-羟基 -3'-(1Η-四唑 -5-基)-联苯基 -3-基] -肼基 }-5-甲基 2-(3,3-Dimethylindan-5-yl) -4 -{[2-hydroxy-3'-(1Η-tetrazol-5-yl)-biphenyl-3-yl]-indole Base}-5-methyl
-2,4-二氢吡唑 -3-酮 -2,4-dihydropyrazole-3-one
冰浴下将 3-氨基 -3'-(1Η-四唑 -5-基)-联苯基 -2-醇盐酸盐 8f (290 mg, 1.0 mmol)溶 解于盐酸 (3.4 mL, 1 mol/L)中， 滴加入 1.2 mL亚硝酸钠溶液 (73 mg, 1.05 mmol), 反 应 10分钟， 再加入 2-(3,3-二甲基茚满 -5-基;) -5-甲基 -2，4-二氢吡唑 -3-酮 8i (218 mg, 0.9 mmol), 分批加入碳酸氢钠 (1.26 g, 15 mmol)和 4.4 mL乙醇， 室温反应 10小时。 TLC跟踪至原料消失， 过滤， 固体用 20 mL水洗涤， 再溶解于 20 mL水中， 冰浴 下用浓盐酸调节 pH<5， 过滤， 干燥， 得到标题产物 2-(3,3-二甲基茚满 -5-基) -4-{[2- 羟基 -3'-(1Η-四唑 -5-基)-联苯基 -3-基] -肼基 }-5-甲基 -2,4-二氢吡唑 -3-酮 8(336 mg，黄
色固体)。 产率:. 73.8%。 3-Amino-3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (290 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/). In L), add 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol), and react for 10 minutes, then add 2-(3,3-dimethylindan-5-yl;)-5-methyl- 2,4-Dihydropyrazol-3-one 8i (218 mg, 0.9 mmol), sodium hydrogencarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and allowed to react at room temperature for 10 hours. TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2-(3,3-dimethyl Indole-5-yl)-4-{[2-hydroxy-3'-(1Η-tetrazol-5-yl)-biphenyl-3-yl]-indenyl}-5-methyl-2, 4-Dihydropyrazol-3-one 8 (336 mg, yellow Color solid). Yield: 73.8%.
MS m/z (ESI): 505 [M-l] MS m/z (ESI): 505 [M-l]
'HNMR(400MHz, DMSO-C 6): 8 1.24(m, 6H), 1.92(t, J=7.2Hz, 2H), 2.36(s, 3H), 2.87(t, J=7.2Hz, 2H), 7.2 l(m, 3H), 7.73(m, 5H), 8.08(d, J=7.6Hz, IH), 8.25(s, IH), 9.77(s, I H): 13.80(s, IH) 实施例 9 'HNMR (400MHz, DMSO-C 6): 8 1.24 (m, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 7.2 l(m, 3H), 7.73(m, 5H), 8.08(d, J=7.6Hz, IH), 8.25(s, IH), 9.77(s, IH): 13.80(s, IH) Example 9
5-{2-羟基 -3-ΓΝ'-Π-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 1-苯基 呋 喃 -2-羧酸 5-{2-hydroxy-3-ΓΝ'-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- Phenylfuran-2-carboxylic acid
9c 9c
第一歩 First
5-(2-甲氧基 -3-硝基苯基) -呋喃 -2-羧酸 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid
将 2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1,3，2]硼酸乙二醇酯 6a (10 g, 35.85 mmol), 5-溴 -呋喃 -2-羧酸 (5.47 g, 28.66 mmol), 四 (三苯基膦)钯 (2.07 g, 1.79 mmol) 和碳酸钠 (7.60 g, 71.66 mmol)溶解于 200 mL 1,4-二氧六环和 30 mL水的混合溶剂 中， 加热回流 2.5小时。 TLC跟踪至原料消失， 过滤， 滤液减压浓缩， 向残余物中 加入 150 mL水， 用 1N盐酸酸化至 pH〜3， 过滤， 固体用 50 mL正己烷和乙酸乙 酯的混合溶剂 (1/1)洗涤， 千燥， 得到标题产物 5-(2-甲氧基 -3-硝基苯基) -呋喃 -2-羧 酸 9a(4.23 g， 灰白色固体；)。 产率： 56.1%。 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (10 g, 35.85 mmol) , 5-bromo-furan-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) dissolved in 200 mL In a mixed solvent of 4-dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. The TLC was traced to the disappearance of the starting material, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of water was added to the residue, acidified to pH~3 with 1N hydrochloric acid, filtered, and mixed with 50 mL of a mixture solvent of n-hexane and ethyl acetate (1/1) The title product was 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, m. Yield: 56.1%.
MS m/z (ESI): 262[M-1] 笛 MS m/z (ESI): 262[M-1] flute
一一丄!^ One by one!^
少 Less
-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸
将 5-(2-甲氧基 -3-硝基苯基) -呋喃 -2-羧酸 9a (4.23 g, 16.09 mmol)溶解于 125mL 乙酸乙酯中， 再加入 423 mg钯 -碳和甲酸铵 (4.054 g, 64.35 mmol) , 加热回流 3.5小 时。 TLC 跟踪至原料消失， 减压浓缩， 用硅胶柱色谱法纯化所得残余物. 得到标 题产物 5-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸 9b(2.79 g，淡绿色固体)，产率： 74.4%。 -(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid Dissolve 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, 16.09 mmol) in 125 mL of ethyl acetate, then add 423 mg of palladium-carbon and ammonium formate. (4.054 g, 64.35 mmol), heated to reflux for 3.5 hours. The residue was evaporated to dryness <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjj , pale green solid), yield: 74.4%.
MS m/z (ESI): 232[M- 1 ] MS m/z (ESI): 232 [M-1]
笛二 Flute
^ _ > -少· ^ _ > - less
5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 将 5-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸 9b (2.79 g, 11.97 mmol)溶解于 25 mL 二氯甲烷中， 滴加入三溴化硼 (23.9 mL, 2.0 mol/L)， 室温反应 1小时。 TLC跟踪至 原料消失， 加入 5 mL甲醇， 减压浓缩， 向残余物中加入 100 mL乙酸乙酯， 搅拌 1 小时， 过滤， 收集固体， 干燥， 得到标题产物 5- 3-氨基 -2-羟基苯基) -呋喃 -2-羧 酸氢溴酸盐 9c (1 .24 g， 黄色固体)。 产率： 47.2%。 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide salt 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 9b ( 2.79 g, 11.97 mmol) was dissolved in 25 mL of dichloromethane, and boron tribromide (23.9 mL, 2.0 mol/L) was added dropwise and allowed to react at room temperature for 1 hour. TLC was traced to the disappearance of the starting material, 5 mL of methanol was added, and concentrated under reduced pressure. 100 mL of ethyl acetate was added to the residue, and the mixture was stirred for 1 hour, filtered, and the solid was collected and dried to give the title product 5- 3-amino-2-hydroxybenzene. -furan-2-carboxylic acid hydrobromide 9c (1.24 g, yellow solid). Yield: 47.2%.
MS m/z (ESI): 218[M- 1] 第四歩 MS m/z (ESI): 218 [M-1] fourth
冰浴下将 5-C3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 9c (300 mg, 1.0 mmol)溶 解于盐酸 (3.4 mL, 1 mol/L)中， 滴加入 1 .2 mL亚硝酸钠溶液 (73 mg, 1.05 mmol), 反 应 10分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (193 mg, 0.9 mmol) , 分批加入碳酸氢钠 (1.26 g, 15 mmol)和 4.4 mL乙醇， 室温反应 24小时。 TLC跟踪 至原料消失， 过滤， 固体用 20 mL水洗涤， 再溶解于 20 mL水中， 冰浴下用浓盐 酸调节 pH<5， 过滤， 干燥， 得到标题产物 5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲基 -5- 氧代 - 1 ,5-二氢吡唑 -4-亚基) -肼基] -苯基 呋喃 -2-羧酸 9(287 mg, 黄色固体)。 产率： 71.8%。 5-C3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (300 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) under ice bath. Add 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol), react for 10 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one (193 mg, 0.9 mmol), sodium hydrogencarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and allowed to react at room temperature for 24 hours. The TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 5-{2-hydroxy-3-[ Ν'-(1-Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenylfuran-2-carboxylic acid 9 (287 mg, yellow solid). Yield: 71.8%.
MS m/z (ESI): 443 [M- l ] MS m/z (ESI): 443 [M- l ]
' HNMR(400MHz, OMSO-d6): δ 2.03(m, 2H), 2.32(s, 3H), 2.89)m, 4H), 7.15(m, 1 H), 7.22(t, J=8.0Hz, 1 H), 7.29(d, J=8.0Hz, 1 H), 7.36(d, J=3.6Hz, 1 H), 7,57(m, 1 H), 7.70(m, 2H), 7.78(s, 1 H), 9.97(s, 1H), 13.73(s, 1 H) 实施例 10 'HNMR (400MHz, OMSO-d6): δ 2.03(m, 2H), 2.32(s, 3H), 2.89)m, 4H), 7.15(m, 1 H), 7.22(t, J=8.0Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 3.6 Hz, 1 H), 7, 57 (m, 1 H), 7.70 (m, 2H), 7.78 (s, 1 H), 9.97 (s, 1H), 13.73 (s, 1 H) Example 10
4- {「2-羟基 -3'-( 1 H-四唑 -5-基)-联苯基 -3-基 1-亚肼基 5-甲基 -2-(5,6,7,8-四氢萘 -2- 基) -2,4-二氢吡唑 -3-酮
冰浴下将 3-氨基 -3'-(1Η-四唑 -5-基)-联苯基 -2-醇盐酸盐 8f (340 mg, 1.34 mmol) 溶解于 3 mL IN盐酸中， 滴加入 3 mL亚硝酸钠溶液 (98 mg, 1.41 mmol), 反应 10 分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (276 mg, 1.21 mmol), 分批加入碳酸氢钠 (1.69 g, 20 mmol)和 3 mL乙醇， 室温反应 18小时。 TLC 跟踪至原料消失， 过滤， 固体用 20 mL水洗涤， 再溶解于 20 mL水中， 冰浴下用 浓盐酸调节 pH=3〜4， 过滤， 干燥， 得到标题产物 4-{[2-羟基 -3'- (1H-四唑 -5-基) - 联苯基 -3-基]-亚肼基 }-5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 10(208 mg, 黄色固体）。 产率： 31.6%。 4- {"2-Hydroxy-3'-( 1 H-tetrazol-5-yl)-biphenyl-3-yl 1-indenyl 5-methyl-2-(5,6,7,8 -tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3-Amino-3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (340 mg, 1.34 mmol) was dissolved in 3 mL of EtOAc. 3 mL of sodium nitrite solution (98 mg, 1.41 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-di Hydropyrazol-3-one 3i (276 mg, 1.21 mmol), sodium hydrogencarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and allowed to react at room temperature for 18 hours. TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 4-{[2-hydroxy- 3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-arylene}-5-methyl-2-(5,6,7,8-tetrahydronaphthalene-2- -2,4-Dihydropyrazol-3-one 10 (208 mg, yellow solid). Yield: 31.6%.
MS m/z (ESI): 491 [M-1] MS m/z (ESI): 491 [M-1]
'HNMR(400MHz, DMSO-i¾: δ 8.19(1H, s), 7.99(1H, s), 7.69(2H, t, .T=8,8), 'HNMR (400 MHz, DMSO-i3⁄4: δ 8.19 (1H, s), 7.99 (1H, s), 7.69 (2H, t, .T=8,8),
7.49(2H，d,J=7.6), 7.15(3H,m), 2.75(4H,m), 2.39(3H,s), 1.75(4H,m) 实施例 11 7.49 (2H, d, J = 7.6), 7.15 (3H, m), 2.75 (4H, m), 2.39 (3H, s), 1.75 (4H, m) Example 11
2'-羟基 -5'-甲基 -3'-W'-f3-甲基 -5-氧代 - 5,6,7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚 2'-Hydroxy-5'-methyl-3'-W'-f3-methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-Asia
11f 第一步 11f first step
2-溴 -4-甲基 -6-硝基苯酚
-5 °C下将硝酸钠 (28 g, 0.33 mmol)溶解于 70 mL浓硫酸和 210 mL水的混合溶 剂中， 缓慢滴加 2-溴 -4-甲基苯酚 11a (30.8 g, 0.165 mol)， 冰浴反应 2小时， 升至室 温反应 1小时。 TLC跟踪至原料消失， 加入 200 mL乙酸乙酯萃取， 有机相用水洗 涤 (100 mLx5;i， 无水硫酸钠干燥， 过滤， 减压浓缩， 用硅胶柱层析分离纯化， 得到 标题产物 2-溴 -4-甲基 -6-硝基苯酚. llb(22.24 g, 黄色固体)。 产率： 58.1 %。 2-bromo-4-methyl-6-nitrophenol Sodium nitrate (28 g, 0.33 mmol) was dissolved in a mixed solvent of 70 mL of concentrated sulfuric acid and 210 mL of water at -5 °C, and 2-bromo-4-methylphenol 11a (30.8 g, 0.165 mol) was slowly added dropwise. The reaction was carried out for 2 hours in an ice bath, and the mixture was allowed to react to room temperature for 1 hour. After the TLC was traced to the disappearance of the starting material, the mixture was extracted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL?? -4-methyl-6-nitrophenol. llb (22.24 g, yellow solid). Yield: 58.1%.
'HNMR(400MHz, DMSO- 6): δ 2.29 ( s,3H ) , 7.81(m,2H), 10.76(s,l H) 第二歩 'HNMR (400MHz, DMSO- 6 ): δ 2.29 ( s, 3H ) , 7.81 (m, 2H), 10.76 (s, l H)
1-溴 -2-甲氧基 -5-甲基 -3-硝基苯 1-bromo-2-methoxy-5-methyl-3-nitrobenzene
将 2-溴 -4-甲基 -6-硝基苯酚 lib (22.24 g, 95.9 mmol)溶解于 150 mL丙酮中， 加 入碳酸钾（15.9 g, 115 mmol)和碘甲垸 (13.7 mL, 220.6 mmol)， 加热回流过夜。 TLC 跟踪至原料消失， 过滤， 滤液减压浓缩， 向残余物中加入 100 mL乙酸乙酯， 再次 过滤， 减压浓缩， 得到标题产物 1-溴 -2-甲氧基 -5-甲基 -3-硝基苯 llc(23.1 g， 橙色 固体)。 产率： 97.9%。 第三步 Dissolve 2-bromo-4-methyl-6-nitrophenol lib (22.24 g, 95.9 mmol) in 150 mL of acetone, add potassium carbonate (15.9 g, 115 mmol) and iodoguanidine (13.7 mL, 220.6 mmol) ), heated to reflux overnight. TLC was traced to the disappearance of the material, filtered, and the filtrate was concentrated under reduced pressure. <RTI ID=0.0>> - Nitrobenzene llc (23.1 g, orange solid). Yield: 97.9%. third step
2'-甲氧基 -5'-甲基 -3'-硝基联苯基 -3-羧酸 2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid
将 溴 -2-甲氧基 -5-甲基 -3-硝基苯 11c (15.0 g, 61 mmol)和间羧基苯硼酸 (11.6 g， 70.1 mmol)溶解于 200mLl,4-二氧六环中， 再加入四 (三苯基膦)钯 (2.8 g， 2.44 mmol)和 61 mL碳酸钠溶液 (12.9 g, 122 mmol), 加热回流过夜。 TLC跟踪至原料消 失， 减压浓缩， 向残余物中加入 500 mL水， 用 150 mL正己烷和 150 mL乙酸乙酯 的混合溶剂洗涤， 再用乙酸乙酯洗涤 (300 mLx2)， 水相用浓盐酸调节 pH至 1〜2， 过滤， 收集固体干燥， 得到标题产物 2'-甲氧基 -5'-甲基 -3'-硝基联苯基 -3-羧酸 lld(15.4 g, 黄色固体）， 产率： 88.1%。 Bromo-2-methoxy-5-methyl-3-nitrobenzene 11c (15.0 g, 61 mmol) and m-carboxyphenylboronic acid (11.6 g, 70.1 mmol) were dissolved in 200 mL of 1,4-dioxane Further, tetrakis(triphenylphosphine)palladium (2.8 g, 2.44 mmol) and 61 mL of sodium carbonate solution (12.9 g, 122 mmol) were added, and the mixture was heated to reflux overnight. TLC was traced to the disappearance of the starting material, concentrated under reduced pressure, and 500 mL of water was added to the residue, washed with a mixture solvent of 150 mL of n-hexane and 150 mL of ethyl acetate, and then washed with ethyl acetate (300 mL×2). Hydrochloric acid was adjusted to pH 1-2, filtered, and the solid was dried to give the title product 2'-methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid lld (15.4 g, yellow solid ), Yield: 88.1%.
'HNMR(400MHz, DMSO-i 6): δ 2.40(s,3H), 3.42(s,3H), 7.58(s,lH), 7.58-7.75(m,lH),'HNMR (400MHz, DMSO-i 6 ): δ 2.40 (s, 3H), 3.42 (s, 3H), 7.58 (s, lH), 7.58-7.75 (m, lH),
7.75(d,J=1.6Hz,lH), 7.82-7.84(m,lH), 8.02(d,J=8Hz,lH), 8.11(d,J=1.6Hz,l H), 7.75 (d, J = 1.6 Hz, lH), 7.82-7.84 (m, lH), 8.02 (d, J = 8 Hz, lH), 8.11 (d, J = 1.6 Hz, l H),
13.12(s,lH) 第四步 13.12(s,lH) Step 4
2'-羟基 -5'-甲基 -3'-硝基联苯基 -3-羧酸 2'-hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid
将 2'-甲氧基 -5'-甲基 -3'-硝基联苯基 -3-羧酸 lid (1 1.2 g, 39.0 mmol)溶解于氢溴 酸溶液 (250 mL， 40%)中， 加热回流过夜。 TLC跟踪至原料消失， 将反应液冷却至 室温， 过滤， 固体用少量水和正己垸洗涤， 干燥， 得到标题产物 2'-羟基 -5'-甲基 -3'- 硝基联苯基 -3-羧酸 lle(9.15 g， 黄色固体)。 产率： 85.9%。 2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid lid (1 1.2 g, 39.0 mmol) was dissolved in hydrobromic acid solution (250 mL, 40%) Heated to reflux overnight. The TLC was traced to the disappearance of the starting material, the reaction mixture was cooled to room temperature, filtered, and the solid was washed with a small amount of water and hexanes and dried to give the title product 2'-hydroxy-5'-methyl-3'-nitrobiphenyl-3 -carboxylic acid lle (9.15 g, yellow solid). Yield: 85.9%.
MS m/z (ESI): 272[M-1] MS m/z (ESI): 272 [M-1]
'HNMR(400MHz, DMSO- 6): 62.36(s,3H),7.60(m,2H), 7.78(d,J=8Hz,lH), 'HNMR (400MHz, DMSO- 6 ): 62.36 (s, 3H), 7.60 (m, 2H), 7.78 (d, J = 8 Hz, lH),
7.88(d,J=1.2Hz,lH), 7.97(d,J=8Hz,lH), 8.11(s,lH), 10.44(s,lH),】3.06(s,l H)
第五步 7.88(d, J=1.2Hz, lH), 7.97(d, J=8Hz, lH), 8.11(s,lH), 10.44(s,lH),]3.06(s,l H) the fifth step
3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 将 2'-羟基 -5'-甲基 -3'-硝基联苯基 -3-羧酸 lie (9.15 g, 33.5 mmol)溶解于 200 mL 乙酸乙酯， 加入 2g钯-碳和甲酸铵 (8.45 g, 134 mmol)， 加热回流 30分钟。 TLC跟 踪至原料消失， 将反应液， 过滤， 滤液用盐酸酸化， 过滤， 干燥， 得到标题产物 3'-氨基 -2'-羟基- 5'-甲基联苯基- 3-羧酸盐酸盐 llf(6.65 g， 白色固体)。 产率： 71.0%。 MS m/z (ESI): 242[M-1] 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 2'-hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylate Acid lie (9.15 g, 33.5 mmol) was dissolved in 200 mL of ethyl acetate, and 2 g of palladium-carbon and ammonium formate (8.45 g, 134 mmol) were added and the mixture was refluxed for 30 minutes. The TLC was traced to the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was acidified with hydrochloric acid, filtered and dried to give the title product 3'-amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride. Llf (6.65 g, white solid). Yield: 71.0%. MS m/z (ESI): 242 [M-1]
'HNMR(400MHz, OMSO-d6): 52.29(s,3H), 7.09(d,J=1.6Hz,lH), 7.14(d,J=1.6Hz,lH), 7.59(t,J=8Hz,lH), 7.74(dd,J,=6.4Hz,J2=l .6Hz,lH), 7.94(dd,J,=6.4Hz,J2=1.6Hz,lH), 8.07(s,lH) 第六步 'HNMR (400MHz, OMSO-d 6 ): 52.29 (s, 3H), 7.09 (d, J = 1.6 Hz, lH), 7.14 (d, J = 1.6 Hz, lH), 7.59 (t, J = 8 Hz, lH), 7.74 (dd, J, = 6.4 Hz, J 2 = 1. 6 Hz, lH), 7.94 (dd, J, = 6.4 Hz, J 2 = 1.6 Hz, lH), 8.07 (s, lH) step
2'-羟基 -5'-甲基 -3'-{N'-[3-甲基- 5-氧代 -l-(5,6,7，8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚 基] -肼基 }-联苯基 -3-羧酸 2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl- 5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,5-dihydropyrazole-4-ylidene]-mercapto}-biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸 盐酸盐 llf (272 mg, 0.97 mmol) 溶解于盐酸 (3.3 mL, 1 mol/L)中， 滴加入 1.3 mL亚硝酸钠溶液 (74 mg, 1.07 mmol), 反应 20分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (200 mg, 0.88 mmol), 分批加入碳酸氢钠 (1.22 g, 14.6 mmol)和 2.1 mL乙醇， 室温反应 4小 时。 TLC跟踪至原料消失， 过滤， 固体用 20mL水洗涤， 再溶解于 20 mL水中， 冰浴下用浓盐酸调节 pH<5， 过滤， 干燥， 得到标题产物 2'-羟基 -5'-甲基 -3'-{N'-[3- 甲基 -5-氧代小 (5,6,7,8-四氢萘 -2-基) -1，5-二氢吡唑 -4-亚基] -肼基 }-联苯基 -3-羧酸 11(170 mg, 红色固体）。 产率： 40.2%。 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride llf (272 mg, 0.97 mmol) was dissolved in hydrochloric acid (3.3 mL, 1 mol/L). Add 1.3 mL of sodium nitrite solution (74 mg, 1.07 mmol) dropwise for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2 4-Dihydropyrazol-3-one 3i (200 mg, 0.88 mmol), sodium hydrogencarbonate (1.22 g, 14.6 mmol) and 2.1 mL of ethanol were added portionwise and allowed to react at room temperature for 4 hours. The TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2'-hydroxy-5'-methyl- 3'-{N'-[3-methyl-5-oxo small (5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene] - mercapto}-biphenyl-3-carboxylic acid 11 (170 mg, red solid). Yield: 40.2%.
MSm/z(ESI): 481[M-1] MSm/z (ESI): 481 [M-1]
'HNMR(400MHz, DMSO- δ 1.75(m, 4Η), 2.30(s, 3H), 2.34(s, 3H), 2.74(m, 4H)， 7.00(d, J=1.2Hz, IH), 7.11(d, J=8.0Hz, IH), 7.53(s, IH), 7.62(m, 3H), 7.80(d, J=7.6Hz, IH), 7.95(d, J=7.6Hz, IH), 8.14(s, IH), 9.39(s, IH), 13,03(s, IH), 13.77(s, IH) 实施例 12 'HNMR (400 MHz, DMSO- δ 1.75 (m, 4 Η), 2.30 (s, 3H), 2.34 (s, 3H), 2.74 (m, 4H), 7.00 (d, J = 1.2 Hz, IH), 7.11 ( d, J=8.0Hz, IH), 7.53(s, IH), 7.62(m, 3H), 7.80(d, J=7.6Hz, IH), 7.95(d, J=7.6Hz, IH), 8.14( s, IH), 9.39(s, IH), 13,03(s, IH), 13.77(s, IH) Example 12
5-(3-{N'-「l-(3,3-二甲基茚满- 5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基 1-肼基 }-2-羟 基苯基) -噻吩 -2-羧酸
5-(3-{N'-"l-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-arylene 1-mercapto}-2-hydroxyphenyl)-thiophene-2-carboxylic acid
12
12
5-(2-甲氧基 -3-硝基苯基) -噻吩 -2-羧酸 5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid
将 2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1 ,3,2]硼酸乙二醇酯 6a(10 g， 35.85 mmol)、 5-溴 -噻吩 -2-羧酸 (6.68 g， 32.2 mmol), 四 (三苯基膦)钯 (2.07 g, 1.79 mmol) 和碳酸钠 (7.59 g, 71.6 mmol)溶解于 200 mL 1 ,4-二氧六环和 30 mL水的混合溶剂 中， 加热回流 1小时。 TLC跟踪至原料消失， 过滤， 滤液减压浓缩， 向残余物中 加入 150 mL水， 用 1N盐酸酸化至 pH = 3， 过滤， 固体用 50 mL正己垸和乙酸乙 酯的混合溶剂 (V:V=1/1)洗涤， 干燥， 得到标题产物 5-(2-甲氧基 - 3-硝基苯基) -噻吩 -2-羧酸 12a (7.7 g， 淡黄色固体)。 产率： 77%。 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1 ,3,2]borate 6a (10 g, 35.85 mmol) , 5-bromo-thiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) dissolved in 200 mL 1 . In a mixed solvent of 4-dioxane and 30 mL of water, the mixture was heated under reflux for 1 hour. TLC was traced to disappearance of the starting material, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 150 mL of water, acidified to pH = 3 with 1N hydrochloric acid, filtered, and mixed with 50 mL of a mixture of hexane and ethyl acetate (V:V 1 / 1) Washing and drying gave the title product 5-(2-methoxy-3-triphenyl)-thiophene-2-carboxylic acid 12a (7.7 g, pale yellow solid). Yield: 77%.
MS m/z (ESI): 277.9[M-1] 第一步 MS m/z (ESI): 277.9 [M-1] first step
5- 3-氨基 -2-甲氧基-苯基) -噻吩 -2-羧酸 5- 3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid
将 5-(2-甲氧基 -3-硝基苯基) -噻吩 -2-羧酸 12a (7.7 g, 27.6 mmol)溶解于 300 mL 乙酸乙酯中， 再加入 500 mg钯 -碳和甲酸铵 (6.96 g, 110 mmol), 加热回流 4小时。 TLC 跟踪至原料消失， 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产 物 5-(3-氨基 -2-甲氧基-苯基) -噻吩 -2-羧酸 12b(6.2 g， 灰色固体)， 产率： 90.1%。 MS m/z (ESI): 248[M-1] 第三歩 Dissolve 5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid 12a (7.7 g, 27.6 mmol) in 300 mL of ethyl acetate, then add 500 mg of palladium-carbon and formic acid Ammonium (6.96 g, 110 mmol) was heated to reflux for 4 h. TLC was traced to the disappearance of the material, and the residue was evaporated. , gray solid), Yield: 90.1%. MS m/z (ESI): 248 [M-1] third
5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 将 5-(3-氨基 -2-甲氧基-苯基) -噻吩 -2-羧酸 12b (2.2 g, 8.83 mmol)溶解于 20 mL 二氯甲垸中， 滴加入三溴化硼 (35 mL, 35.32 mmol/L)， 室温反应 1.5小时。 TLC跟 踪至原料消失， 加入 5 mL甲醇， 减压浓缩， 向残余物中加入 100 mL乙酸乙酯， 搅拌 1.5小时， 过滤， 收集固体， 干燥， 得到标题产物 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c (1.2 g， 灰色固体)。 产率： 57.1%。 5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt 5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 12b ( 2.2 g, 8.83 mmol) was dissolved in 20 mL of dichloromethane, and boron tribromide (35 mL, 35.32 mmol/L) was added dropwise and allowed to react at room temperature for 1.5 hours. TLC was traced to the disappearance of the starting material, and 5 mL of methanol was added, and the mixture was concentrated under reduced pressure. The residue was evaporated. Phenyl)-thiophene-2-carboxylic acid hydrobromide 12c (1.2 g, gray solid). Yield: 57.1%.
MS m/z (ESI): 234[M-1 ]
第四步 MS m/z (ESI): 234 [M-1] the fourth step
5— 二甲基茚满—5—基 3-甲基 -5—氧代 -1,5—二氢吡唑 -4—亚基 ] -肼基 }-2—羟 5-dimethylindan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2 -hydroxyl
. 基苯基) -噻吩 -2-羧酸 . phenyl)-thiophene-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c (171 mg, 0.62 mmol) 溶解于 3 mL盐酸 (IN)中， 滴加入 1 mL亚硝酸钠溶液 (47 mg, 0.68 mmol) , 搅拌 20 分钟， 再加入 2-(3 3-二甲基茚满 -5-基) -5-甲基 -2 4-二氢吡唑 -3-酮 8i (150 mg, 0.62 mmol), 分批加入饱和碳酸氢钠溶液 (781 mg, 9.3 mmol)将 pH调至 8 9， 用 2 mL 乙醇淬灭气泡， 升至室温反应过夜。 TLC 跟踪至原料消失， 过滤出固体， 固体用 20 mL水溶解， 浓盐酸调 pH = 3 4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得到 标题产物 5-(3- {N'-[l-(3,3-二甲基茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] - 肼基 2-羟基苯基) -噻吩 -2-羧酸 12 (48 mg， 橙色固体)。 产率： 15.9% Dissolve 5-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (171 mg, 0.62 mmol) in 3 mL hydrochloric acid (IN) under ice-cooling, add 1 mL dropwise Sodium nitrite solution (47 mg, 0.68 mmol), stirred for 20 minutes, then added 2-(3 3-dimethylindan-5-yl)-5-methyl-2-dihydropyrazole-3- Ketone 8i (150 mg, 0.62 mmol), aq. EtOAc (EtOAc, EtOAc, EtOAc) TLC was traced to disappearance of the starting material, the solid was filtered out, the solid was dissolved in 20 mL of water, and the mixture was adjusted to pH = 3 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 5-(3- {N'-[l- (3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indolyl 2-hydroxyphenyl) - Thiophene-2-carboxylic acid 12 (48 mg, orange solid). Yield: 15.9%
MS m/z (ESI): 487[M-1] MS m/z (ESI): 487 [M-1]
'HNMR(400MHz, DMSO-i (5): 51.24(t,J=8.6,6H), 1.93(t,J=7.0,2H), 2.87(t,J=7.0,2H), 7.16(m,J=6.0,lH), 7.27(d,J=4.2,2H), 7.57(d,J=8.0,lH), 7.64(d,J=4.0,lH), 'HNMR (400 MHz, DMSO-i (5): 51.24 (t, J = 8.6, 6H), 1.93 (t, J = 7.0, 2H), 2.87 (t, J = 7.0, 2H), 7.16 (m, J) =6.0, lH), 7.27 (d, J = 4.2, 2H), 7.57 (d, J = 8.0, lH), 7.64 (d, J = 4.0, lH),
7.70(t,J=8.4,2H), 7.75(d,J=4.0,lH) 实施例 13 7.70 (t, J = 8.4, 2H), 7.75 (d, J = 4.0, lH) Example 13
3'-{Ν'-『1- 3-二氢苯并呋喃 -5-基 3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基 1-肼基 }- 2'-羟 3'-{Ν'-"1- 3-Dihydrobenzofuran-5-yl 3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 1-indenyl}- 2'-hydroxyl
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 llf (287 mg, 1.03 mmol) 溶解于 3.5 mL盐酸 (IN)中， 滴加入 1.5 mL亚硝酸钠溶液 (78 mg, 1.13 mmol), 搅拌 20分钟， 再加入 2-(2 3-二氢苯并呋喃 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 7c (200 mg, 0.93 mmol), 分批加入饱和碳酸氢钠溶液 (1.298 g, 15.45 mmol)将 pH调至 8 9， 用 2 mL乙醇淬灭气泡， 升至室温反应过夜。 TLC跟踪至原料消失， 过滤出固体， 用 20 mL水溶解， 搅拌均匀， 用浓盐酸调 pH = 3 4, 过滤， 干燥， 固体用 10 mL二 氯甲烷和甲醇混合溶剂 (V:V=1 : 1)洗涤， 粗品用 HPLC 分离纯化， 得到标题产物 3'-{Ν'-[1-(2,3-二氢苯并呋喃 -5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基] -肼基 }-2'-羟
基- 5'-甲基联苯基 -3-羧酸 13 (100 mg, 红色固体)。 产率： 23.0%。 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride llf (287 mg, 1.03 mmol) was dissolved in 3.5 mL of hydrochloric acid (IN) under ice bath, and added dropwise 1.5 mL of sodium nitrite solution (78 mg, 1.13 mmol), stirred for 20 minutes, then added 2-(2 3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 7c (200 mg, 0.93 mmol), EtOAc (EtOAc m. TLC was traced to disappearance of the starting material, the solid was filtered off, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 4 with concentrated hydrochloric acid, filtered, dried, and mixed with 10 mL of dichloromethane and methanol (V:V = 1: 1) Washing, crude product was purified by HPLC to give the title product 3'-{Ν'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1 ,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxyl Base - 5'-methylbiphenyl-3-carboxylic acid 13 (100 mg, red solid). Yield: 23.0%.
MS m/z (ESI): 469[M-1] MS m/z (ESI): 469 [M-1]
'HNMR(400MHZ, DMSO-i/6): δ 2.34(s, 3H), 2.36(s, 3H), 3.24(t, J=8.8Hz, 2H), 4.57(t, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, IH), 7.00(s, IH), 7.54(s, IH), 7.61 (m, 2H), 7.74(s, 1H): 7.80(d, J=7.6Hz, IH), 7.95(d, J=7.6Hz, IH), 8.13(s， IH), 9.38(s, IH), 13.02(s, IH), 13.76(s, IH) 实施例 14'HNMR (400 MHZ, DMSO-i/6): δ 2.34 (s, 3H), 2.36 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H) , 6.82 (d, J = 8.8 Hz, IH), 7.00 (s, IH), 7.54 (s, IH), 7.61 (m, 2H), 7.74 (s, 1H) : 7.80 (d, J = 7.6 Hz, IH), 7.95 (d, J = 7.6 Hz, IH), 8.13 (s, IH), 9.38 (s, IH), 13.02 (s, IH), 13.76 (s, IH) Example 14
N'-「l-(2,3-二氢苯并呋喃 -5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基卜肼基 }-5'-氟 N'-"l-(2,3-Dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-indolyl}-5' -fluorine
-2'-羟基联苯基 -3-羧酸 -2'-hydroxybiphenyl-3-carboxylic acid
MS m/z (ESI): 473 [M-l] MS m/z (ESI): 473 [M-l]
'HNMR(400MHz, DMSO-i/(5): δ 2.33(s, 3H), 3.23(t, J=8.8Hz, 2H), 4.56(t, J=8.8Hz, 2H), 6.83(d, J=8,4Hz, IH), 7.03(m, IH), 7.48(m, IH), 7.60(m, 2H), 7.65(s, IH), 7.83(d, J=8.0Hz, IH), 7.98(d, J=8.0Hz, IH), 8.17(s, IH), 9.57(s, IH), 13.07(s, 1H)， 13.62(s, IH) 实施例 15 'HNMR (400MHz, DMSO-i/(5): δ 2.33(s, 3H), 3.23(t, J=8.8Hz, 2H), 4.56(t, J=8.8Hz, 2H), 6.83(d, J =8,4Hz, IH), 7.03(m, IH), 7.48(m, IH), 7.60(m, 2H), 7.65(s, IH), 7.83(d, J=8.0Hz, IH), 7.98( d, J=8.0 Hz, IH), 8.17 (s, IH), 9.57 (s, IH), 13.07 (s, 1H), 13.62 (s, IH) Example 15
5-〔2-羟基- 3-{N'-「3-甲基 -5-氧代小 (5.6.7,8-四氢萘 -2-基) -1 ,5-二氢吡唑 -4-亚基卜肼 5-[2-hydroxy-3-{N'-"3-methyl-5-oxo small (5.6.7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4 -Yakib
基 苯基) -呋喃 -2-羧酸
Phenyl)-furan-2-carboxylic acid
ac 3i 15 Ac 3i 15
冰浴下将 5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 9c (292 mg, 0.975 mmol) 溶解于 3.3 mL盐酸 (IN)中， 滴加入 1.3 mL亚硝酸钠溶液 (74 mg, 1.07 mmol), 搅拌 20分钟， 再加入 5-甲基- 2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (200 mg, 0.88 mmol), 分批加入饱和碳酸氢钠溶液 (1.226 g, 14.6 mmol)将 pH调至 8〜9， 用 2 mL 乙醇淬灭气泡， 升至室温反应过夜。 TLC跟踪至原料消失， 过滤出固体， 用 20 mL 水溶解， 搅拌均匀， 用浓盐酸调 pH = 3〜4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得到标题产物 5-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1-(5,6,7,8-四氢萘 -2-基) -1 ,5-二氢吡唑 -4-亚基]-肼基 苯基) -呋喃 -2-羧酸 15 (160 mg， 红色固体)。 产率： 39.8%。 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (292 mg, 0.975 mmol) was dissolved in 3.3 mL hydrochloric acid (IN) under ice-cooling, and added dropwise to 1.3 mL Sodium nitrite solution (74 mg, 1.07 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyridyl Zyridin-3-one 3i (200 mg, 0.88 mmol), portionwise added saturated sodium bicarbonate solution (1.226 g, 14.6 mmol), pH adjusted to 8~9, quenched with 2 mL of ethanol, and allowed to react to room temperature overnight. . TLC was traced to the disappearance of the starting material, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and purified and purified by HPLC to give the title product 5-(2-hydroxy-3) -{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene] -nonylphenyl)-furan-2-carboxylic acid 15 (160 mg, red solid). Yield: 39.8%.
MS m/z (ESI): 457[M-1] MS m/z (ESI): 457 [M-1]
'HNMR(400MHz, DMSO- 6): δ 1.76(m, 4Η), 2.33(s, 3H), 2.75(m, 4H), 7.13(m, 2H), 7.22(t, J=8.0Hz, IH), 7.37(d, J=3.2Hz, IH), 7.56(d, J=7.6Hz, IH), 7.63(m, 2H), 7.71(d, J=8.4Hz, IH) 实施例 16 'HNMR (400MHz, DMSO-6): δ 1.76 (m, 4 Η), 2.33 (s, 3H), 2.75 (m, 4H), 7.13 (m, 2H), 7.22 (t, J = 8.0 Hz, IH) , 7.37 (d, J = 3.2 Hz, IH), 7.56 (d, J = 7.6 Hz, IH), 7.63 (m, 2H), 7.71 (d, J = 8.4 Hz, IH) Example 16
3'-ίΝ'-「1-(3.3-二甲基茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基 1-肼基 2'-羟基 3'-ίΝ'-"1-(3.3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 1-indenyl 2'-hydroxyl
-5'-甲基联苯基 -3-羧酸 -5'-methylbiphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 llf (257 mg, 0.92 mmol)
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J=7.6Hz, IH), 7.98(d, J=8.0Hz, IH), 8.18(s, I H), 9.60(s, I H), 13.07(br, 1H)， 13.64(s: IH) 实施例 .18 100000/600ZN3/X3d J = 7.6 Hz, IH), 7.98 (d, J = 8.0 Hz, IH), 8.18 (s, IH), 9.60 (s, IH), 13.07 (br, 1H), 13.64 (s : IH). 18
5- {2-羟基 1 - -S- -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 1-苯基 噻 吩 -2-羧酸 5-{2-Hydroxy 1 - -S--3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1-phenylthiophene-2-carboxylic acid
12c 18 12c 18
冰浴下，将 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c(380 mg, 1.2 mmol) 溶解于 3.9 mL盐酸 (IN)中， 滴加入 1.5 mL亚硝酸钠溶液 (90 mg, 1.32 mmol), 搅拌 20分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (210 mg, 1 mmol), 分批 加入饱和碳酸氢钠溶液 (1.51 g， 18 mmol)将 pH调至 8〜9， 用 2 mL乙醇淬灭气泡， 升至室温反应过夜。 TLC跟踪至原料消失， 过滤出固体， 用 20 mL 5 %氢氧化钠溶 液溶解，水相用二氯甲垸萃取 (50 mL>O)，水相用浓盐酸调 pH = 3〜4，过滤，干燥， 粗品用 HPLC分离纯化，得到标题产物 5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基] -苯基 噻吩 -2-羧酸 18 (15 mg,橙色固体)。产率： 3.3%。 MS m/z (ESI): 459[M-1] 5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (380 mg, 1.2 mmol) was dissolved in 3.9 mL hydrochloric acid (IN) and added dropwise to 1.5. mL of sodium nitrite solution (90 mg, 1.32 mmol), stir for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (210 mg, 1 mmol), a saturated sodium bicarbonate solution (1.51 g, 18 mmol) was added portionwise to adjust the pH to 8~9, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. TLC was traced to disappearance of the starting material, the solid was filtered off, dissolved in 20 mL of 5 % sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (50 mL > O), the aqueous phase was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, and filtered. Dry and crude product were purified by HPLC to give the title product 5-{2-hydroxy-3-[Ν'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro Pyrazol-4-ylidene)-indenyl]-phenylthiophene-2-carboxylic acid 18 (15 mg, orange solid). Yield: 3.3%. MS m/z (ESI): 459 [M-1]
'HNMR(400MHz, DMSO-i¾: 61.36-1.78(m,2H), 2.33(s,3H), 2.86-2.94(m,4H), 7.17(t,J=8Hz,lH), 7.30(d,J=8Hz,lH), 7.56(dd,J,=8Hz,J2=0.8Hz,lH), 7.56(d,J=4Hz, lH), 7.70(m,2H), 7.75(d,J=4Hz,lH), 7.79(s,lH) 实施例 19 'HNMR (400 MHz, DMSO-i3⁄4: 61.36-1.78 (m, 2H), 2.33 (s, 3H), 2.86-2.94 (m, 4H), 7.17 (t, J = 8 Hz, lH), 7.30 (d, J) =8 Hz, lH), 7.56 (dd, J, = 8 Hz, J 2 = 0.8 Hz, lH), 7.56 (d, J = 4 Hz, lH), 7.70 (m, 2H), 7.75 (d, J = 4 Hz, lH), 7.79(s,lH) Example 19
2'-羟基 -3'-{Ν'-Γ3-甲基 -5-氧代 -1-(U.3，3-四甲基茚满 -5-基) -1,5-二氢吡唑 -4-亚基卜肼 2'-Hydroxy-3'-{Ν'-Γ3-methyl-5-oxo-1-(U.3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole -4-Yakib
第一步 First step
5-溴 -3,3-二甲基茚满 -1 -酮 5-bromo-3,3-dimethylindan-1-one
将 6-溴 -1,1-二甲基茚满 8g (4g， 17.8 mmol)溶解于 40 mL重蒸的二氯甲垸中， 加入氧化铬 (280 mg， 1.8 mmol), 缓慢滴加过氧化叔丁醇 (19 mL, 190 mmol)， 反应 液呈深红色， 有气体放出， 密闭反应， 室温下搅拌过夜。 TLC 跟踪至原料消失， 将反应液中加入 50 mL水稀释， 用二氯甲垸萃取 (100 mLx3)， 合并的有机相通过 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到标题产物 5-溴 -3,3-二甲基茚满 -1-酮 19a (3.5 g, 白色固体)， 产率： 82.3 %。 Dissolve 6-bromo-1,1-dimethylindane 8g (4g, 17.8 mmol) in 40 mL of re-distilled dichloromethane, add chromium oxide (280 mg, 1.8 mmol), slowly add peroxide. tert-Butyl alcohol (19 mL, 190 mmol), the reaction mixture was dark red, with a gas evolved, and sealed, and stirred at room temperature overnight. The TLC was traced to the disappearance of the starting material, and the reaction mixture was diluted with 50 mL of water, and extracted with dichloromethane (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate. Bromo-3,3-dimethylindan-1-one 19a (3.5 g, white solid), Yield: 82.3%.
MS m/z (ESI): 238[M-1] f¾一少 MS m/z (ESI): 238[M-1] f3⁄4 less
5-溴 -1,1,3,3-四甲基茚满 5-bromo-1,1,3,3-tetramethylindan
将 40 mL二氯甲垸用乙腈 -干冰冷却至 -40°C，注射器加入四氯化钛 (2.7 mL， 24.6 mmol), 冷却下搅拌 20分钟后加入二甲基锌 (29.3 mL,35.1 mmol)甲苯溶液， 控制反 应在 -30Ό下，滴加完毕后低温反应 30分钟，加入 5-溴 -3,3-二甲基茚满 -1-酮 19a (2.8 g, 11.7 mmol)的 10 mL二氯甲烷溶液， 反应缓慢升至室温， 反应过夜。 TLC跟踪 至原料消失， 将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯化， 得到标题产物 5-溴 -1,1,3,3-四甲基茚满 19b (1.55g， 无色油状液体)， 产率： 52.3 %。 MS m/z (ESI): 252[M-1 ] 第三步 40 mL of dichloromethane was cooled to -40 ° C with acetonitrile-dry ice, titanium tetrachloride (2.7 mL, 24.6 mmol) was added to the syringe, and the mixture was stirred under cooling for 20 minutes, then dimethylzinc (29.3 mL, 35.1 mmol) was added. Toluene solution, control reaction at -30 Torr, low temperature reaction for 30 minutes after addition, add 5-bromo-3,3-dimethylindan-1-one 19a (2.8 g, 11.7 mmol) of 10 mL of dichloro The methane solution was slowly warmed to room temperature and allowed to react overnight. The residue was evaporated to dryness under reduced pressure. g, colorless oily liquid), Yield: 52.3 %. MS m/z (ESI): 252[M-1 ] Step 3
1-(1 ,1,3，3-四甲基 -2,3-二氢 -1H-茚满 -5-基)肼基 -1,2-二甲酸二叔丁酯 将 5-溴 -1,1 , 3,3-四甲基茚满 19b (1.4g， 5.53 mmol) 溶于 10 mL四氢呋喃中， 在 丙酮-干冰浴冷却至 -78°C， 滴加叔丁基锂 (4.4 mL， 11.1 mmol), 搅拌 40分钟， 恒 压漏斗滴加偶氮二甲酸二叔丁酯 (1.59g, 6.92 mmol)的 10 mL四氢呋喃溶液， -78°C
下继续反应 3小时。 TLC跟踪至原料消失， 加入 5mL甲醇， 反应液升至室温， 用 乙酸乙酯萃取 (20 mLx3)反应液， 合并的有机相用无水硫酸钠干燥， 过滤， 减压下 浓缩， 用硅胶柱层析分离纯化， 得到标题产物 1 -(1 ,1 ,3,3-四甲基 -2,3-二氢 -1H-茚满 -5-基)肼基 -1 ,2-二甲酸二叔丁酯 19c (1.326 g， 黄色油状液体)。 产率： 59.3%。 5-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indenyl-1,2-dicarboxylic acid di-tert-butyl ester 5-bromo-1 1,1,3,3-tetramethylindan 19b (1.4g, 5.53 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to -78 ° C in acetone-dry ice bath, and added t-butyl lithium (4.4 mL, 11.1) Ment), stirring for 40 minutes, a constant pressure funnel was added dropwise a solution of di-tert-butyl azodicarboxylate (1.59 g, 6.92 mmol) in 10 mL of tetrahydrofuran, -78 ° C The reaction was continued for 3 hours. The residue was evaporated to dryness. Separation and purification gave the title product 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indolyl-1,2-dicarboxylic acid di-tert-butyl Ester 19c (1.326 g, yellow oily liquid). Yield: 59.3%.
MS m/z (ESI): 403 [M+l ] 第四步 MS m/z (ESI): 403 [M+l ] Step 4
5-甲基 -2-(1,1,3,3-四甲基茚满 -5基) -2,4-二氢吡唑 -3-酮 将 1-(1山3,3-四甲基 -2,3-二氢 -1H-茚满 -5-基)肼基 -1,2-二甲酸二叔丁酯 19c (2.70 g, 7.18 mmol)溶解于 10 mL乙酸中，加入 13 mL三氟乙酸，室温反应 30分钟， 加入乙酰乙酸乙酯 (502 mg, 3.86 mmol), 加热至 100Ό反应 2小时。 TLC跟踪至原 料消失， 冷却至室温， 减压浓缩除去乙酸， 用饱和碳酸氢钠溶液中和反应液中的 酸， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤， 无水硫酸 钠干燥， 过滤， 滤液减压浓缩， 所得残余物用硅胶柱色谱法纯化， 得到标题产物 5-甲基 -2-(1 ,1,3,3-四甲基茚满 -5基) -2，4-二氢吡唑- 3-酮 19d (130 mg， 淡黄色油状液 体)。 产率： 13.6%。 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one will 1-(1山三,3-四甲Base 2,3-dihydro-1H-indan-5-yl) decyl-1,2-dicarboxylic acid di-tert-butyl ester 19c (2.70 g, 7.18 mmol) was dissolved in 10 mL of acetic acid, then added 13 mL The fluoroacetic acid was reacted at room temperature for 30 minutes, and ethyl acetoacetate (502 mg, 3.86 mmol) was added, and the mixture was heated to 100 Torr for 2 hours. The TLC was traced to the disappearance of the starting material, cooled to room temperature, and concentrated under reduced pressure to remove acetic acid. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate (20 mL×3), and the organic phase was combined with saturated sodium chloride solution The organic layer was dried (MgSO4jjjjjjjjjjjjjj 5-yl)-2,4-dihydropyrazole-3-one 19d (130 mg, light yellow oily liquid). Yield: 13.6%.
MS m/z (ESI): 269[M+1] 第五步 MS m/z (ESI): 269[M+1] Step 5
2'-羟基 -3'-{N'-[3-甲基- 5-氧代 -1-(1,1,3,3-四甲基茚满 -5-基) -1,5-二氢吡唑 -4-亚基] -肼 基}-联苯基— 3-羧酸 2'-hydroxy-3'-{N'-[3-methyl- 5-oxo-1-(1,1,3,3-tetramethylindan-5-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (172 mg, 0.56 mmol)溶解于 1.9 mL IN盐酸中， 滴加入的 0.7 mL亚硝酸钠溶液 (42 mg, 0.61 mmol), 再加入 5- 甲基 -2-(1,1,3,3-四甲基茚满 -5基) -2,4-二氢吡唑 -3-酮 19d (135 mg, 0.5 mmol), 分批 加入碳酸氢钠 (700 mg， 8.33 mmol), 将反应液 pH调至 8〜9， 加入 2 mL乙醇， 升 至室温过夜。 TLC跟踪至原料消失， 过滤， 固体用 20 mL水溶解， 搅拌均匀， 用 浓盐酸调 pH = 3〜4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得到标题产物 2'-羟基 -3'-{N'-[3-甲基 -5-氧代 -1-(1 ,1 ,3,3-四甲基茚满 -5-基) -1,5-二氢吡唑 -4-亚基] -肼基 }4关 苯基 -3-羧酸 19 (75 mg， 红色固体；)。 产率： 29.4%。 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (172 mg, 0.56 mmol) was dissolved in 1.9 mL of IN hydrochloric acid under ice bath, and 0.7 mL of sodium nitrite solution was added dropwise. (42 mg, 0.61 mmol), followed by 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one 19d ( 135 mg, 0.5 mmol), sodium bicarbonate (700 mg, 8.33 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8~9, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. TLC was traced to disappearance of the starting material, filtered, and the solid was dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then purified and purified by HPLC to give the title product 2'-hydroxy-3'-{ N'-[3-Methyl-5-oxo-1-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene] - mercapto} 4 off phenyl-3-carboxylic acid 19 (75 mg, red solid;). Yield: 29.4%.
MS m/z (ESI): 509[M-1 ] MS m/z (ESI): 509 [M-1 ]
'HNMR(400MHz, DMSO- δ 1.30(m, 12H), 1.92(s, 2H)， 2.35(s, 3H), 7.14(m, 2H)， 7.23(d, J=8.0Hz, 1H)， 7.62(m, 2H), 7.72(m, 2H), 7.80(d, J=7.6Hz, 1H), 7.96(d, J=8.0Hz; 1H), 8.14(s, 1H)， 9.68(s, 1H), 13.10(br, 1H), 13.78(s, 1H) 实施例 20 'HNMR (400 MHz, DMSO- δ 1.30 (m, 12H), 1.92 (s, 2H), 2.35 (s, 3H), 7.14 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.62 ( m, 2H), 7.72 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.0 Hz ; 1H), 8.14 (s, 1H), 9.68 (s, 1H), 13.10(br, 1H), 13.78(s, 1H) Example 20
2'-羟基 -5'-甲基 -3'-{Ν'-Γ3-甲基 -5-氧代 -1 -0,1,3,3-四甲基茚满 -5-基) -1 ,5-二氢吡唑 -4- 亚基 1-肼基 }-联苯基 -3-羧酸
2'-Hydroxy-5'-methyl-3'-{Ν'-Γ3-methyl-5-oxo-1 -0,1,3,3-tetramethylindan-5-yl) -1 ,5-dihydropyrazol-4-ylidene 1-indolyl}-biphenyl-3-carboxylic acid
MS m/z (ESI): 523 [M-l] MS m/z (ESI): 523 [M-l]
'HNMR(400MHz, OMSO-d6): δ 1.30(m, 12H), 1.92(s, 2H), 2.35(m, 6H), 7.00(m, 1H), 7.23(d, J=8.4Hz, 1H), 7.59(s, 1H), 7.65(m, 2H), 7.74(m, 1H), 7.80(d, J=8.0Hz, 1H), 7.95(d, J=7.6Hz, 1H), 8.14(s, 1H), 9.4 l(s, 1H), 13.05(br, 1H)， 13.78(s, 1H) 实施例 21 'HNMR (400MHz, OMSO-d6): δ 1.30(m, 12H), 1.92(s, 2H), 2.35(m, 6H), 7.00(m, 1H), 7.23(d, J=8.4Hz, 1H) , 7.59(s, 1H), 7.65(m, 2H), 7.74(m, 1H), 7.80(d, J=8.0Hz, 1H), 7.95(d, J=7.6Hz, 1H), 8.14(s, 1H), 9.4 l(s, 1H), 13.05(br, 1H), 13.78(s, 1H) Example 21
3'-[ '- Π -双环「4.2.01辛烷 -1，3.5-三烯 -3-基 -3-甲基 -5-氧代- 1 ,5-二氢吡唑 -4-亚基) -肼 基卜 2'-羟基 -5'-甲基联苯基 -3-羧酸 3'-[ '- Π -bicyclo"4.2.01 Octane-1,3.5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ) - 肼基卜 2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid
'HNMR(400MHz, DMSO-t 6): δ 2.34(m, 6H), 3.16(m, 4H)， 7.00(s, 1H), 7.15(d, J=8.0Hz, 1H), 7.54(s, 1H), 7.62(m, 2H), 7.71(d, J=8.0Hz, 1H), 7.80(d, J=7.6Hz, 1H), 7.95(d, J=7.6Hz, 1H)， 8.13(s, 1H), 9.40(s, 1H), 13.02(s, 1H), 13.75(s, 1H) 实施例 22 'HNMR (400MHz, DMSO-t 6): δ 2.34(m, 6H), 3.16(m, 4H), 7.00(s, 1H), 7.15(d, J=8.0Hz, 1H), 7.54(s, 1H ), 7.62(m, 2H), 7.71(d, J=8.0Hz, 1H), 7.80(d, J=7.6Hz, 1H), 7.95(d, J=7.6Hz, 1H), 8.13(s, 1H) ), 9.40(s, 1H), 13.02(s, 1H), 13.75(s, 1H) Example 22
5-Π-1Ν'-Π-双环 Γ4.2.01辛垸 -U，5-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) - 肼基 1-2-羟基苯基 呋喃 -2-羧酸 5-Π-1Ν'-Π-bicyclic Γ4.2.01 垸-U,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-subunit ) - mercapto 1-2-hydroxyphenylfuran-2-carboxylic acid
9c 9c
5d 22 冰浴下将 5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 9c (333 mg, 1.11 mmol) 溶解于 3.7 mLlN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (84 mg, 1.22 mmol), 再加 入 2-双环 [4.2.0]辛垸 -1(6),2，4-三烯 -3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 5d (200 mg, 1 mmol), 分批加入碳酸氢钠 (1.4 g， 16.7 mmol), 将反应液 pH调至 8〜9， 力 Π入 2 mL 乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过滤出固体， 用 20 mL水溶解， 搅 拌均匀， 用浓盐酸调 pH = 3〜4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得到标题 产物 5-{3-[Ν'-(1-双环 [4.2.0]辛垸 -1,3,5-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚 基)-肼基] -2-羟基苯基} -呋喃 -2-羧酸 22(275 mg， 暗红色固体)。 产率： 63.9%。 5d 22 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise to 1.5 mL. Sodium nitrate solution (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl-2,4-di Hydropyrazol-3-one 5d (200 mg, 1 mmol), sodium bicarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8~9, and 2 mL of ethanol was added to room temperature. overnight. TLC was traced to disappearance of the starting material, the solid was filtered off, dissolved in 20 mL of water, stirred well, adjusted to pH = 3~4 with concentrated hydrochloric acid, filtered, dried, and then purified and purified by HPLC to give the title product 5-{3-[Ν' -(1-bicyclo[4.2.0]octyl-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) - mercapto]-2-hydroxyphenyl}-furan-2-carboxylic acid 22 (275 mg, dark red solid). Yield: 63.9%.
MS m/z (ESI): 429ΓΜ-1]
'H MR(400MHz, DMSO-t/(5): δ 2.3 l (s, 3H), 3.15(m, 4H), 7.15(m, 2H), 7.20(t, J=8.0Hz, 1H), 7.36(d, J=3.6Hz, 1H), 7.54(m, 1H), 7.68(m, 1H), 7.72(m, 2H), 9.97(s, 1H), 13.71(s, 1H) 实施例 23 MS m/z (ESI): 429ΓΜ-1] 'H MR (400 MHz, DMSO-t/(5): δ 2.3 l (s, 3H), 3.15 (m, 4H), 7.15 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.54 (m, 1H), 7.68 (m, 1H), 7.72 (m, 2H), 9.97 (s, 1H), 13.71 (s, 1H) Example 23
2-双环「4.2.01 辛垸 -1 5-三烯 -3-基 -4-ί「2-羟基 -3'-ΠΗ-四唑 -5-基) -联苯 -3-基卜 亚肼 2-bicyclic "4.2.01 辛垸-1 5-trien-3-yl-4-ί" 2-hydroxy-3'-indole-tetrazol-5-yl)-biphenyl-3-pyabazin
基}-5-甲基 -2,4-二氢吡唑 -3-酮 }--5-methyl-2,4-dihydropyrazole-3-one
8f 5d 23 8f 5d 23
冰浴下将 3-氨基 -3'- (1H-四唑 -5-基) -联苯基 -2-醇盐酸盐 8f (321 mg, 1.11 mmol) 溶解于 3.7 mL IN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 反应 20分钟，再加入 2-双环 [4.2.0]辛垸 -1(6),2,4-三烯 -3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 5d (200 mg, 1 mmol), 分批加入碳酸氢钠（1.69 g, 20 mmol)和 3 mL乙醇， 室温反应过 夜。 TLC跟踪至原料消失， 过滤， 固体用 20mL水洗涤， 再溶解于 20mL水中， 冰 浴下用浓盐酸调节 pH=3〜4， 过滤， 干燥， 得到标题产物 2-双环 [4.2.0] 1,3,5- 三烯—3-基 -4-{[2-羟基 -3'-(1Η-四唑 -5-基) -联苯 -3-基]- 亚肼基 }-5-甲基 -2,4-二氢吡唑 -3-S 23 (150 mg, 红色固体）。 产率： 32.3%。 3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (321 mg, 1.11 mmol) was dissolved in 3.7 mL of IN hydrochloric acid and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-A Base-2,4-dihydropyrazol-3-one 5d (200 mg, 1 mmol), sodium bicarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and dried to give the title product 2-bis[[. 3,5-Triene-3-yl-4-{[2-hydroxy-3'-(1Η-tetrazol-5-yl)-biphenyl-3-yl]-arylene}-5-methyl -2,4-dihydropyrazole-3-S 23 (150 mg, red solid). Yield: 32.3%.
MS m/z (ESI): 463 [M-1] MS m/z (ESI): 463 [M-1]
'HNMR(400MHz, DMSO-t/d): 5 2.34(s, 3Η), 3.16(m, 4H), 7.18(m, 3H), 7.68(s, 1H), 7.73(m, 4H), 8.08(d, J=7.6Hz, 1H)， 8.25(d, J=10Hz, 1H), 9.71(br, 1H), 13.77(br, 1H) 实施例 24 'HNMR (400MHz, DMSO-t/d): 5 2.34(s, 3Η), 3.16(m, 4H), 7.18(m, 3H), 7.68(s, 1H), 7.73(m, 4H), 8.08( d, J = 7.6 Hz, 1H), 8.25 (d, J = 10 Hz, 1H), 9.71 (br, 1H), 13.77 (br, 1H) Example 24
5-{2-羟基 -3-ΓΝ'-Π-茚满 -5-基 -3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基) -肼基 1-5-甲基苯 5-{2-hydroxy-3-ΓΝ'-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- 5-methylbenzene
第一步 First step
2-(2-甲氧基 -5-甲基 -3-硝基苯基 )-4,4,5,5-四甲基 -1,3,2-二氧硼戊环 将 3-溴 -2-甲氧基 -5-甲基-硝基苯 11c (20 g, 81.3 mmol)和 4,4,4',4，,5,5,5，,5，-八甲 基 -2,2，-联 -1,3,2-硼酸乙二醇酯 (30.9 g, 112 mmol)溶解于 400 mL二甲醚中， 加入 1，Γ-双 (二苯膦基)二茂铁二氯化钯 (3.3 g, 4.06 mmol)和醋酸钾 (19.9 g， 203 mmol), 加毕加热回流 3小时， 反应液过滤除去 Ι ,Γ-双 (二苯膦基)二茂铁二氯化钯， 滤液减 压浓缩后经硅胶柱色谱法纯化得到标题产物 3-(4,5-二甲基 -[1,3,2]硼酸频那醇酯 -2- 基) -2-甲氧基 -5-甲基-硝基苯 24a(13.1 g， 黄色油状液体)， 产率 57.1 %。 2-(2-methoxy-5-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3-bromo- 2-methoxy-5-methyl-nitrobenzene 11c (20 g, 81.3 mmol) and 4,4,4',4,5,5,5,5,-octamethyl-2,2 ,-linked-1,3,2-boronic acid ethylene glycol ester (30.9 g, 112 mmol) was dissolved in 400 mL of dimethyl ether, and 1, bis-bis(diphenylphosphino)ferrocene palladium dichloride was added. (3.3 g, 4.06 mmol) and potassium acetate (19.9 g, 203 mmol), heated and refluxed for 3 hours, and the reaction solution was filtered to remove hydrazine, bis-bis(diphenylphosphino)ferrocene palladium chloride, and the filtrate was reduced. After concentration by pressure, purification by silica gel column chromatography gave the title product 3-(4,5- dimethyl-[1,3,2]boronic acid benzoate-2-yl)-2-methoxy-5- Base-nitrobenzene 24a (13.1 g, yellow oily liquid), yield 57.1%.
MS m/z (ESI): 293.09 [M+ l] MS m/z (ESI): 293.09 [M+ l]
'HNMR(400MHz, CDCI3): δ 1.16(s,12H), 2.39(s,3H), 3.5(s,3H), 7.53(d,J=2Hz,lH), 7.83(d,J=2Hz,lH) 第二步 'HNMR (400MHz, CDCI3): δ 1.16(s,12H), 2.39(s,3H), 3.5(s,3H), 7.53(d,J=2Hz,lH), 7.83(d,J=2Hz,lH ) the second step
5-(3-硝基 -2-甲氧基 -5-甲基苯基) -噻吩 -2-羧酸 将 3-(4,5-二甲基 -[1,3,2]硼酸频那醇酯 -2-基) -2-甲氧基 -5-甲基-硝基苯 24a (4.0 g, 14.5 mmol)、 5-溴 -噻吩 -2-羧酸 (1.0 g, 4.8 mmol).四 (三苯基膦)钯 (0.276 g， 0.24 mmol) 和碳酸钠（1.01 g， 9.6 mmol)溶解于 30 mLl,4-二氧六环和 10 mL水中， 反应体系加 热回流 1小时， TLC跟踪至原料消失，反应液减压浓缩后加水溶解，过滤除去四 (三 苯基膦：)钯， 滤液用乙酸乙酯萃取， 水相经酸化后有固体析出， 固体用乙酸乙酯溶 解， 经无水硫酸锾干燥， 过滤除去干燥剂， 滤液浓缩得到标题产物 5-(3-硝基 -2-甲 氧基 -5-甲基苯基) -噻吩 -2-羧酸 24b(1.03 g， 黄色固体)， 产率： 73.6%。 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 3-(4,5-dimethyl-[1,3,2]boronic acid Alcohol ester-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (4.0 g, 14.5 mmol), 5-bromo-thiophene-2-carboxylic acid (1.0 g, 4.8 mmol). (Triphenylphosphine) palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL of 1,2-dioxane and 10 mL of water, and the reaction was heated to reflux for 1 hour. The raw material disappeared, and the reaction liquid was concentrated under reduced pressure, and then dissolved with water, and then filtered to remove tetras(triphenylphosphine:) palladium. The filtrate was extracted with ethyl acetate. After the aqueous phase was acidified, solid was precipitated and solid was dissolved in ethyl acetate. The sulphate was dried, the residue was filtered, and the filtrate was concentrated to give the title product 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24b (1.03 g, yellow solid) , Yield: 73.6%.
MS m/z (ESI): 291.7[M-1] MS m/z (ESI): 291.7 [M-1]
'HNMR(400MHz, CDCI3): δ 2.41(s,3H), 3.73(s,3H), 7.73-7.79(m,3H), 8.00(m,l H), 13.20(Br,lH) 第三步 'HNMR (400MHz, CDCI3): δ 2.41(s,3H), 3.73(s,3H), 7.73-7.79(m,3H), 8.00(m,l H), 13.20(Br,lH)
5-C3-氨基 -2-甲氧基 -5-甲基苯基) -噻吩 -2-羧酸 将 5-(3-硝基 -2-甲氧基 -5-甲基苯基) -噻吩 -2-羧酸 24b(0.29 g, 1 mmol)溶解于
30mL乙酸乙酯中， 加入 0.06 g钯 -碳和甲酸垵 (0.25 g, 4 mmol), 加毕加热回流 45 分钟。 TLC跟踪至原料消失， 过滤除去钯 -碳， 滤液减压浓缩， 干燥， 得到标题产 物 5-(3-氨基 -2-甲氧基 -5-甲基苯基) -噻吩 -2-羧酸 24c(0.26 g，绿色固体)。产率： 99%。 MS m/z (ESI): 261.7[M-1] 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene 2-carboxylic acid 24b (0.29 g, 1 mmol) dissolved in To 30 mL of ethyl acetate, 0.06 g of palladium-carbon and cesium formate (0.25 g, 4 mmol) were added, and the mixture was heated and refluxed for 45 minutes. The TLC was traced to the disappearance of the starting material, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24c. (0.26 g, green solid). Yield: 99%. MS m/z (ESI): 261.7 [M-1]
'HNMR(400MHz, CDC13): δ 2.18(s,3H), 3.58(s,3H), 6.54(d,J=1.6Hz,lH), 'HNMR (400 MHz, CDC1 3 ): δ 2.18 (s, 3H), 3.58 (s, 3H), 6.54 (d, J = 1.6 Hz, lH),
6.78(d,J=1.6Hz,lH), 7.53(d,.T=4Hz,lH), 7.68(d,J=4Hz,lH) 第四步 6.78 (d, J = 1.6 Hz, lH), 7.53 (d, .T = 4 Hz, lH), 7.68 (d, J = 4 Hz, lH)
5-(3-氨基 -2-羟基 -5-甲基苯基)-噻吩 -2-羧酸氢溴酸盐 将 5-(3-氨基 -2-甲氧基 -5-甲基苯基) -噻吩 -2-羧酸 24c (0.26 g, 1 mmol)溶解于 20 mL二氯甲烷中， 滴加入三溴化硼 (5 mL, 35.32 mmol/L), 室温反应 1小时。 TLC 跟踪至原料消失， 减压浓缩， 向残余物中加入 30mL乙酸乙酯， 搅拌 0.5小时， 过 滤， 滤饼用乙酸乙酯洗涤后干燥， 得到标题产物 5-(3-氨基 -2-羟基 -5-甲基苯基) -噻 吩 -2-羧酸氢溴酸盐 24d (0.15 g， 灰色固体)。 产率： 45.5%。 5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide salt 5-(3-amino-2-methoxy-5-methylphenyl) - Thiophene-2-carboxylic acid 24c (0.26 g, 1 mmol) was dissolved in 20 mL of dichloromethane, and boron tribromide (5 mL, 35.32 mmol/L) was added dropwise and allowed to react at room temperature for 1 hour. The title material disappeared to give the titled product 5-(3-amino-2-hydroxy--~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5-Methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (0.15 g, gray solid). Yield: 45.5%.
MS m/z (ESI): 247.8[M-1] MS m/z (ESI): 247.8 [M-1]
'HNMR(400MHz, CDCI3): 52.29(s,3H), 7.02(d,J=1.6Hz,lH), 7.41(s,lH), 'HNMR (400MHz, CDCI3): 52.29 (s, 3H), 7.02 (d, J = 1.6 Hz, lH), 7.41 (s, lH),
7.59(d,J=4Hz,lH), 7.73(d,J=4Hz,lH) 第五歩 7.59 (d, J = 4 Hz, lH), 7.73 (d, J = 4 Hz, lH)
5-{2-羟基 -3-[N'-(l-茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 ]-5-甲基苯 基} -噻吩 -2-羧酸 5-{2-hydroxy-3-[N'-(l-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-fluorenyl ]-5-methylphenyl}-thiophene-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基 -5-甲基苯基) -噻吩 -2-羧酸氢溴酸盐 24d (138 mg, 0.42 mmol) 溶解于 1.5 mL IN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol),反应 20分钟，再加入 2-茚满 -5-基 -5-甲基 -2，4-二氢吡唑 -3-酮 li (81 mg, 0.38 mmol), 分批加入碳酸氢钠 (527 mg, 6.27 mmol)和 2 mL乙醇， 室温反应过夜。 TLC 跟踪至原料消失， 过滤， 固体用 20mL水洗涤， 再溶解于 10mL水中， 冰浴下用浓 盐酸调节 Ph=3〜4， 过滤， 干燥， 得到标题产物 5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲 基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 ]-5-甲基苯基} -噻吩 -2-羧酸 24 (30 mg,红色固 体)。 产率： 16.7%。 Dissolve 5-(3-amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (138 mg, 0.42 mmol) in 1.5 mL of IN hydrochloric acid under ice bath, drop Add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (81 Mg, 0.38 mmol), sodium hydrogencarbonate (527 mg, 6.27 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 10 mL of water, and adjusted to Ph = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 5-{2-hydroxy-3-[ Ν'-(1-Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]-5-methylphenyl} Thiophene-2-carboxylic acid 24 (30 mg, red solid). Yield: 16.7%.
MS m/z (ESI): 473 [M-l] MS m/z (ESI): 473 [M-l]
"HNM (400MHz, DMSO-ί/ό): δ 2.03(m, 2H), 2.32(s, 3H), 2.36(s, 3H), 2.89(m, 4H), 7.29(d, J=8.0Hz, 1H), 7.38(s, 1H), 7.50(s, 1H), 7.63(d, J=4.0Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.74(m, 2H), 9.78(s, 1H), 13.72(br, 1H) . 实施例 25 "HNM (400MHz, DMSO-ί/ό): δ 2.03(m, 2H), 2.32(s, 3H), 2.36(s, 3H), 2.89(m, 4H), 7.29(d, J=8.0Hz, 1H), 7.38(s, 1H), 7.50(s, 1H), 7.63(d, J=4.0Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.74(m, 2H), 9.78( s, 1H), 13.72(br, 1H) . Example 25
5-(2-轻基 -3-{N'-D-甲基 -5-氧代 -1-(U,3.3-四甲基茚满 -5-基) -1 ,5-二氢吡唑 -4-亚基 肼基 μ苯基 呋喃 -2-羧酸
5-(2-light-based-3-{N'-D-methyl-5-oxo-1-(U,3.3-tetramethylindan-5-yl)-1,5-dihydropyrazole -4-ylidene thiol-phenylfuran-2-carboxylic acid
'HNMR(400MHz, DMSO- 6): δ 1.30(m, 12H), 1.92(s, 2H), 2.34(s, 3H), 7.15(d, J=3.6Hz, 1H), 7.22(m, 2H), 7.36(d, J=3.2Hz, 1H), 7.56(dd, Jl=8.0Hz, J2=1.2Hz, 1H), 7.66(d, J=2.0Hz, 1H), 7.75(m, 2H) 实施例 26 'HNMR (400MHz, DMSO-6): δ 1.30 (m, 12H), 1.92 (s, 2H), 2.34 (s, 3H), 7.15 (d, J = 3.6 Hz, 1H), 7.22 (m, 2H) , 7.36 (d, J = 3.2 Hz, 1H), 7.56 (dd, Jl = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.75 (m, 2H) 26
3'— ΓΝ'-Π -双环「4.2.01辛烷 -1,3,5-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基)- 肼 基卜 5'-氟 -2'-羟基联苯 -3-羧酸 3 '- ΓΝ'-Π-bicyclic "4.2.01 Octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit)- 肼基卜 5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid
26
26
26 26
第一歩 First
3'-氨基 -5'-氟 -2'-羟基联苯基 -3-羧酸氢溴酸盐 3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide
将实施例 2第五步所得中间体 3'-氨基 -5'-氟 -2'-羟基联苯基 -3-羧酸 2f(500 mg, 1.92 mmol) 滴加 20 mL氢溴酸， 有白色浑浊物生成， 加热回流反应过夜， 反应澄 清， 变为黄褐色溶液。 TLC 跟踪至原料消失， 减压下浓缩溶液， 得到的棕黄色固 体用 20 mL乙酸乙酯溶解， 搅拌 20分钟， 过滤， 得到标题产物 3'-氨基 -5'-氟 -2'-羟 基联苯基 -3-羧酸氢溴酸盐 26a (344 mg， 灰白色固体)。 产率： 54.8%。 The intermediate 3'-amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (500 mg, 1.92 mmol) obtained in the fifth step of Example 2 was added dropwise with 20 mL of hydrobromic acid, white The turbidity was formed, heated to reflux overnight, and the reaction was clarified to a yellow-brown solution. TLC was traced to the disappearance of the starting material, and the solution was concentrated under reduced pressure. The obtained brown solid was dissolved in ethyl acetate (20 mL), stirred for 20 min and filtered to give the title product 3'-amino-5'-fluoro-2'-hydroxybiphenyl. Base-3-carboxylic acid hydrobromide 26a (344 mg, off-white solid). Yield: 54.8%.
MS m/z (ESI): 248 [M+l] 第二步 MS m/z (ESI): 248 [M+l] Step 2
3'-[N'-(l -双环 [4.2.0]辛烷 -1,3,5-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) - 肼基] -5'-氟 -2'-羟基-二苯基 -3-羧酸 3'-[N'-(l-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole -4-subunit) - fluorenyl] -5'-fluoro-2'-hydroxy-diphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -5'-氟 -2'-羟基联苯基 -3-羧酸氢溴酸盐 26a (328 mg, 1.11 mmol) 溶解于 3.7 mL IN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (84 mg, 1.22 mmol), 再加 入 2-双环 [4.2.0]辛垸 -1(6)，2,4-三烯 -3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 5d (200 mg, 1 mmol), 分批加入碳酸氢钠 (1.4 g， 16.7 mmol), 将反应液 pH调至 8〜9， 加入 2 mL 乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过滤出固体， 用 20 mL水溶解， 搅 拌均勾， 用浓盐酸调 pH = 3〜4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得到标题 产物 3'-[Ν'-(1-双环 [4.2.0]辛烷 -1,3,5-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚 基) - 肼基] -5'-氟 -2'-羟基联苯 -3-羧酸 26 (335 mg， 红色固体)。 产率： 73.1%。 Dissolve 3'-amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 26a (328 mg, 1.11 mmol) in 3.7 mL of IN hydrochloric acid and add 1.5 mL dropwise. Sodium nitrite solution (84 mg, 1.22 mmol), followed by 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl-2,4- Dihydropyrazol-3-one 5d (200 mg, 1 mmol), sodium bicarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8~9, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. . After TLC traced to the disappearance of the starting material, the solid was filtered off, dissolved in 20 mL of water, stirred, and adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then purified and purified by HPLC to give the title product 3'-[Ν'- (1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) - Indenyl] -5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 26 (335 mg, red solid). Yield: 73.1%.
MS m/z (ESI): 457[M-1] MS m/z (ESI): 457 [M-1]
'HNMR(400MHz, DMSO- δ 2.32(s, 3H), 3.22(m, 4H), 7.02(m, 1H), 7.14(d, J=8.0Hz, 1H), 7.46(m, 1 H), 7.6 l(m, 2H), 7.69(m, 1 H), 7.82(d, J=7, 6Hz, 1H), 7.98(d, J=7.6Hz, 1H), 8.17(s, 1 H), 9.58(s, 1H), 13.07(s, 1H), 13.60(s, 1H) 实施例 27
4- 2-羟基 -3'-ΠΗ-四唑 -5-基)-联苯 -3-基 1-肼叉 }-2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 'HNMR (400MHz, DMSO- δ 2.32 (s, 3H), 3.22 (m, 4H), 7.02 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.46 (m, 1 H), 7.6 l(m, 2H), 7.69(m, 1 H), 7.82(d, J=7, 6Hz, 1H), 7.98(d, J=7.6Hz, 1H), 8.17(s, 1 H), 9.58( s, 1H), 13.07(s, 1H), 13.60(s, 1H) Example 27 4- 2-hydroxy-3'-indole-tetrazol-5-yl)-biphenyl-3-yl 1-indole}-2-indan-5-yl-5-methyl-2,4-di Hydropyrazole
-3-酮 -3-ketone
冰浴下将 3-氨基 -3'-(1Η-四唑 -5-基)-联苯基 -2-醇盐酸盐 8f (188 mg, 0.74 mmol) 溶解于 4 mL 2N盐酸中， 滴加入 1 mL亚硝酸钠溶液 (57 mg, 0.82 mmol), 反应 30 分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (159 mg, 0.74 mmol), 用饱 和碳酸氢钠调节 pH值至 8， 加入 0.5 mL乙醇， 室温反应过夜。 TLC跟踪至原料 消失， 过滤， 固体用氢氧化钠溶液 (3N)溶解后用二氯甲烷洗涤 3次， 水相用 2N盐 酸调节 pH值至 3，有大量固体析出，过滤，所得固体经柱层析得到标题产物 4-{[2- 羟基 -3'-(1Η-四唑 -5-基) -联苯 -3-基]-肼叉 }-2-茚满 -5-基 -5-甲基- 2,4-二氢吡唑 -3-酮 27(67 mg, 橙色固体）， 产率： 18.8%。 3-Amino-3'-(1Η-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (188 mg, 0.74 mmol) was dissolved in 4 mL of 2N hydrochloric acid and added dropwise. 1 mL of sodium nitrite solution (57 mg, 0.82 mmol), react for 30 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (159 mg , 0.74 mmol), the pH was adjusted to 8 with saturated sodium bicarbonate, and 0.5 mL of ethanol was added and allowed to react overnight at room temperature. TLC was traced to disappearance of the starting material, filtered, and the solid was dissolved in sodium hydroxide solution (3N) and washed with dichloromethane three times. The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid. A large amount of solid was precipitated and filtered. The title product 4-{[2-hydroxy-3'-(1Η-tetrazol-5-yl)-biphenyl-3-yl]-anthracene}-2-indan-5-yl-5-- Base-2,4-dihydropyrazol-3-one 27 (67 mg, orange solid), Yield: 18.8%.
MS m/z (ESI): 477.2[M-1] MS m/z (ESI): 477.2 [M-1]
'HNMR(400MHz, DMSO-ί/ό): δ 2.03(m, 2H), 2.33(s, 3H), 2.89(m, 4H), 7.17(m, 2H), 7.28(d, J=8.0Hz, 1H), 7.71(m, 5H), 8.08(d, J-8.0Hz,】H), 8.25(s, 1H), 9.73(br, 1H), 13.77(s, 1H) 实施例 28 'HNMR (400MHz, DMSO-ί/ό): δ 2.03(m, 2H), 2.33(s, 3H), 2.89(m, 4H), 7.17(m, 2H), 7.28(d, J=8.0Hz, 1H), 7.71(m, 5H), 8.08(d, J-8.0Hz, H), 8.25(s, 1H), 9.73(br, 1H), 13.77(s, 1H) Example 28
4-(2-羟基 -3-W'-「3-甲基 -5-氧代 -l-(5,6，7，8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚 基 1-肼基 苯基) -呋喃 -2-羧酸 4-(2-hydroxy-3-W'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5- Dihydropyrazole-4-ylidene 1-indolylphenyl)-furan-2-carboxylic acid
4-溴 -呋喃 -2-羧酸 4-bromo-furan-2-carboxylic acid
室温下， 将 4,5-二溴-呋喃 -2-羧酸 28a(5.5 g， 20.3 mmol)和 18 mL氨水加入到 63 mL水中， 加入锌粉（1.46 g， 22.33 mmol), 加毕室温搅拌 6小时， TLC监测至 原料反应完全， 停止反应。 用盐酸 (1N)调节反应液 pH至 3， 有大量固体析出， 过 滤，滤饼用正己垸洗涤 (15 mLx4)后干燥，得到标题产物 4-溴 -呋喃 -2-羧酸 28b(3.2 g， 白色固体)， 产率： 83.1 %。 4,5-dibromo-furan-2-carboxylic acid 28a (5.5 g, 20.3 mmol) and 18 mL of aqueous ammonia were added to 63 mL of water at room temperature, zinc powder (1.46 g, 22.33 mmol) was added, and the mixture was stirred at room temperature. After 6 hours, the TLC was monitored until the reaction of the starting material was complete and the reaction was stopped. The pH of the reaction mixture was adjusted to 3 with hydrochloric acid (1N), and a large solid was precipitated, filtered, and the filter cake was washed with n-hexane (15 mL×4) and dried to give the title product 4-bromo-furan-2-carboxylic acid 28b (3.2 g, White solid), Yield: 83.1%.
MS m/z (ESI): 188.7[M-1] 第二步 MS m/z (ESI): 188.7 [M-1] Step 2
4-(3-硝基 -2-甲氧基-苯基) -呋喃 -2-羧酸 4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid
将 2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1,3,2]硼酸乙二醇酯 6a (4 g, 14.34 mmol) , 4-溴 -呋喃 -2-羧酸 28b(2.18 g, 1 1.47 mmol)、 四（三苯基膦)钯 (829 mg， 0.717 mmol)和碳酸钾 (3.96 g, 28.68 mmol)溶解于 80 mL 1 ,4-二氧六环和 30mL水的混合溶 剂中， 加热回流 2.5小时。 TLC跟踪至原料消失， 反应液用 1N盐酸酸化至 pH〜3， 乙酸乙酯萃取 (80 mLx3) , 合并有机相， 有机相减压浓缩后柱层析得到标题产物 4-(3-硝基 -2-甲氧基-苯基)-呋喃- 2-羧酸 28c(3.42 g， 棕色油状液体)。 产率： 90.7%。 MS m/z (ESI): 261.8[M-1] 第三歩 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (4 g, 14.34 mmol) , 4-bromo-furan-2-carboxylic acid 28b (2.18 g, 1 1.47 mmol), tetrakis(triphenylphosphine)palladium (829 mg, 0.717 mmol) and potassium carbonate (3.96 g, 28.68 mmol) dissolved in 80 mL In a mixed solvent of 1, 4-dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. The TLC was traced to the disappearance of the starting material, and the reaction mixture was acidified to pH~3 with 1N hydrochloric acid, ethyl acetate (yield: 80 mL×3), the organic phase was combined, and the organic phase was concentrated under reduced pressure to give the title product 4-(3-nitro- 2-Methoxy-phenyl)-furan-2-carboxylic acid 28c (3.42 g, brown oily). Yield: 90.7%. MS m/z (ESI): 261.8 [M-1] third
4-0氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸 4-0 amino-2-methoxy-phenyl)-furan-2-carboxylic acid
将 4-(3-硝基 -2-甲氧基-苯基) -呋喃 -2-羧酸 28c(500 mg, 1.9 mmol)溶解于 15mL 乙酸乙酯中， 再加入 100 mg钯 -碳和甲酸铵 (429 mg, 7.6 mmol), 加热回流 3小时。 TLC跟踪至原料消失， 反应液过滤除去耙 /碳， 减压浓缩得到标题产物 4-(3-氨基 -2- 甲氧基-苯基) -呋喃 -2-羧酸 28d(325 mg， 黄色油状液体)， 产率： 73.4%。 Dissolve 4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (500 mg, 1.9 mmol) in 15 mL of ethyl acetate and then add 100 mg of palladium-carbon and formic acid Ammonium (429 mg, 7.6 mmol) was heated to reflux for 3 h. The TLC was traced to the disappearance of the starting material, and the reaction mixture was filtered to remove hydrazine/carbon, and concentrated under reduced pressure to give the title product 4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, yellow oil Liquid), Yield: 73.4%.
MS m/z (ESI): 231.8[M-1] 第四歩
4-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 MS m/z (ESI): 231.8 [M-1] 歩 4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide
将 4-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸 28d (325 mg, 1.4 mmol)溶解于 5 mL 二氯甲垸中， 滴加入三溴化硼 (2.8 mL, 5.6 mmol), 室温反应 4.5小时。 TLC跟踪至 原料消失， 加入 5 mL甲醇， 减压浓缩， 向残余物中加入 10 mL乙酸乙酯， 搅拌 0.5 小时， 过滤， 收集固体， 干燥， 得到标题产物 4-(3-氨基 -2-羟基苯基) -呋喃 -2- 羧酸氢溴酸盐 28e(174 mg, 灰色固体)。 产率： 57.1%。 4-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, 1.4 mmol) was dissolved in 5 mL of dichloromethane, and boron tribromide (2.8) was added dropwise. mL, 5.6 mmol), reacted at room temperature for 4.5 hours. TLC was traced to the disappearance of the starting material, and 5 mL of methanol was added, and the mixture was concentrated under reduced pressure. The residue was evaporated and evaporated. Phenyl)-furan-2-carboxylic acid hydrobromide 28e (174 mg, gray solid). Yield: 57.1%.
MS m/z (ESI): 217.7[M-1] 第五歩 MS m/z (ESI): 217.7 [M-1] 歩
4-(2-羟基 -3-{Ν'- [3-甲基 -5-氧代 -1-(5,6,7,8-四氢萘亚甲基 -2-基)- 1 ,5-二氢吡唑 -4-亚 基] -肼基 }-苯基) -呋喃 -2-羧酸 4-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1 ,5 -dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid
冰浴下将 4-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 28e (170 mg, 0.57 mmol) 溶解于盐酸 (1.9 mL, 1 mol/L)中， 滴加入 0.7 mL亚硝酸钠溶液 (43 mg, 0.63 mmol), 反应 20分钟， 再加入 5-甲基 -2-(5，6，7,8-四氢萘 -2-基)- 2,4-二氢吡唑 -3-酮 3i (116 mg, 0.51 mmol), 用饱和碳酸氢钠溶液调节 pH至 8〜9, 加入 2 mL乙醇， 室温反应 24 小时。 TLC跟踪至原料消失， 过滤， 固体中加入 15 mL水， 冰浴下用浓盐酸调节 pH至 2〜3， 过滤， 滤饼用乙酸乙酯洗涤， 干燥， 得到标题产物 4-(2-羟基 -3-{N'-[3- 甲基 -5-氧代 -1-(5,6,7,8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚基] -肼基 }-苯基) -呋 喃 -2-羧酸 28(13 mg， 红色固体)。 产率： 5.5%。 4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7 mL of sodium nitrite solution (43 mg, 0.63 mmol) was added dropwise for 20 minutes, and then 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4 was added. -Dihydropyrazol-3-one 3i (116 mg, 0.51 mmol), the pH was adjusted to 8~9 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, filtered, and 15 mL of water was added to the solid. The pH was adjusted to 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-(2-hydroxy- 3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4 -subunit]-mercapto}-phenyl)-furan-2-carboxylic acid 28 (13 mg, red solid). Yield: 5.5%.
MS m/z (ESI): 456.7[M-1] MS m/z (ESI): 456.7 [M-1]
'HNMR(400MHz, DMSO-t/6): δ 1.75(m,4H), 2.31(s,3H), 2.78(m,4H), 3.86(s,3H), 7.13(m,2H), 7.43(d,J=7.6Hz,lH), 7.62(m,2H), 7.78(s,lH), 8.43(s,lH), 9.68(br,lH), 13.73(br,lH) 实施例 29 'HNMR (400MHz, DMSO-t/6): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.78 (m, 4H), 3.86 (s, 3H), 7.13 (m, 2H), 7.43 ( d, J = 7.6 Hz, lH), 7.62 (m, 2H), 7.78 (s, lH), 8.43 (s, lH), 9.68 (br, lH), 13.73 (br, lH) Example 29
2'-羟基 -3'-ΓΝ'-Π-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 1-5'-甲基 -联苯 2'-Hydroxy-3'-ΓΝ'-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1-5 '-Methyl-biphenyl
-3-羧酸 3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 llf (346 mg, 1.07 mmol)
溶解于盐酸 (5 mL, 2 mol/L)中， 滴加入 2 mL亚硝酸钠溶液 (81 mg, 1.17 mmol), 反 应 30分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (229 mg, 1.07 mmol), 用饱和碳酸氢钠溶液调节 pH值至 8， 加入 5 mL乙醇， 室温反应过夜。 TLC跟踪 至原料消失， 过滤， 固体用乙醇洗涤， 滤液倒入冰水中， 用 1 N盐酸调节 pH值至 4， 有固体析出， 过滤， 所得固体用乙酸乙酯洗涤 3 次， 干燥后得到标题产物 2'- 羟基 -3'-[Ν'-(1-茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 ]-5'-甲基 -联苯 -3-羧酸 29(75 mg， 红色固体)。 产率： 15%。 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride llf (346 mg, 1.07 mmol) in ice bath Dissolve in hydrochloric acid (5 mL, 2 mol/L), add 2 mL of sodium nitrite solution (81 mg, 1.17 mmol), react for 30 minutes, then add 2-indan-5-yl-5-methyl- 2,4-Dihydropyrazol-3-one li (229 mg, 1.07 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 5 mL of ethanol was added and allowed to react overnight at room temperature. The TLC was traced to the disappearance of the starting material, filtered, and the solid was washed with ethanol. The filtrate was poured into ice water, and the pH was adjusted to 4 with 1 N hydrochloric acid. The solid was precipitated and filtered, and the obtained solid was washed three times with ethyl acetate. 2'-Hydroxy-3'-[Ν'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl] -5'-Methyl-biphenyl-3-carboxylic acid 29 (75 mg, red solid). Yield: 15%.
MS m/z (ESI): 467.2 [M-1 ] MS m/z (ESI): 467.2 [M-1]
'HNMR(400MHz, DMSO-C 6): δ 2.01(m, 2H), 2.35(m, 6H), 2.88(m, 4H), 6.97(s, 1H), 7.30(s, 1H), 7.70(m, 5H)， 8.02(s, 1H), 8.15(s, 1H), 9.42(br, 1H)， 13.03(br, 1H), 13.77(s, 1H) 实施例 30 'HNMR (400MHz, DMSO-C 6): δ 2.01 (m, 2H), 2.35 (m, 6H), 2.88 (m, 4H), 6.97 (s, 1H), 7.30 (s, 1H), 7.70 (m) , 5H), 8.02 (s, 1H), 8.15 (s, 1H), 9.42 (br, 1H), 13.03 (br, 1H), 13.77 (s, 1H) Example 30
3WN'-ri-(3,3-二甲基茚满 -5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基卜肼基 2'-羟基 联苯 -3-羧酸 3WN'-ri-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 2'-hydroxyl linkage Benzene-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (310 mg, 1.0 mmol)溶解于 盐酸 (3.4 mL, 1 mol/L)中，滴加入 1.2 mL亚硝酸钠溶液 (73 mg, 1.05 mmol),反应 10 分钟， 再加入 2-(3,3-二甲基茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 8i (218 mg, 0.9 mmol),分批加入碳酸氢钠 (1.26 g, 15 mmol)和 4.4 mL乙醇，室温反应 10小时。 TLC 跟踪至原料消失， 过滤， 固体用 20 mL水洗涤， 再溶解于 20 mL水中， 冰浴下用 浓盐酸调节 pH<5， 过滤， 干燥， 得到标题产物 3'-{Ν'-[1-(3,3-二甲基茚满 -5-基) -3- 甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 }-2'-羟基联苯 -3-羧酸 30(500 mg, 黄色固 体)。 产率： 94%。 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (310 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) under ice bath, and added dropwise to 1.2 mL sodium nitrite solution (73 mg, 1.05 mmol), react for 10 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 8i (218 mg, 0.9 mmol), sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and reacted at room temperature for 10 hours. TLC was traced to disappearance of the starting material, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 3'-{Ν'-[1- (3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxyl linkage Benzene-3-carboxylic acid 30 (500 mg, yellow solid). Yield: 94%.
MS mix (ESI): 509.1 [M-1] MS mix (ESI): 509.1 [M-1]
'HNMR(400MHz, DMSO-C?(5): δ 1.24(m, 6H), 1.92(t, J=7.2Hz, 2H), 2.34(s, 3H)， 2.86(t, J=7.2Hz, 2H), 7.16(m, 2H), 7.25(d, J=8.8Hz, 1 H), 7.62(t, J=7.6Hz, 1H)， 7.70(m, 3H), 7.80(d, J=7.6Hz, 1H), 7.96(d, J=7.2Hz, 1H), 8.14(s, 1H), 9.68(s, 1H) 实施例 31
4-{2-羟基 -3- Γ '-Π-茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 1-苯 呋喃 'HNMR (400MHz, DMSO-C?(5): δ 1.24(m, 6H), 1.92(t, J=7.2Hz, 2H), 2.34(s, 3H), 2.86(t, J=7.2Hz, 2H ), 7.16(m, 2H), 7.25(d, J=8.8Hz, 1 H), 7.62(t, J=7.6Hz, 1H), 7.70(m, 3H), 7.80(d, J=7.6Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 9.68 (s, 1H) Example 31 4-{2-hydroxy-3- Γ '-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- Phenfuran
-2-羧酸 2-carboxylic acid
冰浴下将 4-(3-氨基- 2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 28e (170 mg, 0.57 mmol) 溶解于盐酸 (1.9 mL, 1 mol/L)中， 滴加入 0.7 mL亚硝酸钠溶液 (43 mg, 0.63 mmol), 反应 20分钟，再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (109 mg, 0.51 mmol), 用饱和碳酸氢钠溶液调节 pH至 8〜9, 加入 2 mL乙醇， 室温反应 24小时。 TLC 跟踪至原料消失， 过滤， 固体中加入 15 mL水， 冰浴下用浓盐酸调节 pH至 2〜3 , 过滤， 滤饼用乙酸乙酯洗涤， 干燥， 得到标题产物 4-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3- 甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基] -苯 呋喃- 2-羧酸 31(83 mg, 黑色固体)。 产率： 36.7%。 4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7 mL of sodium nitrite solution (43 mg, 0.63 mmol) was added dropwise for 20 minutes, followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li ( 109 mg, 0.51 mmol), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, filtered, and 15 mL of water was added to the solid. The pH was adjusted to 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-{2-hydroxy- 3-[Ν'-(1-Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-benzol-2- Carboxylic acid 31 (83 mg, black solid). Yield: 36.7%.
MS m/z (ESI): 442.8[M-1] MS m/z (ESI): 442.8 [M-1]
'HNMR(400MHz, DMSO- 6): δ 2.08(m,2H), 2.32(s,3H), 2.89(m,4H), 'HNMR (400MHz, DMSO-6): δ 2.08 (m, 2H), 2.32 (s, 3H), 2.89 (m, 4H),
7.13(t,J=8.0Hz,lH), 7.28(d,J=8.4Hz,lH), 7.41(d,J=7.6Hz,lH), 7.65(m,3H), 7.75(m,lH), 8.37(s,lH), 9.68(s,lH), 13.22(br,l H), 13.74(s,lH) 实施例 32 7.13 (t, J = 8.0 Hz, lH), 7.28 (d, J = 8.4 Hz, lH), 7.41 (d, J = 7.6 Hz, lH), 7.65 (m, 3H), 7.75 (m, lH), 8.37 (s, lH), 9.68 (s, lH), 13.22 (br, l H), 13.74 (s, lH) Example 32
4-{「4'-(4，5-二氫 -1H-咪唑 -2-基 2-羟基联苯 -3-基 1-肼叉 }-2-茚满 -5-基 -5-甲基 -2,4-二 氢吡唑 -3-酮 4-{"4'-(4,5-Dihydro-1H-imidazol-2-yl 2-hydroxybiphenyl-3-yl-1-indole}-2-indan-5-yl-5-methyl -2,4-dihydropyrazol-3-one
3'-硝基 -2'-甲氧基 -联苯 -4-甲醛 3'-nitro-2'-methoxy-biphenyl-4-carbaldehyde
室温下， 将 4-甲酰基苯硼酸 (3.0 g， 0.02 mol) , 1-溴 -2-甲氧基 -3-硝基苯 lc(4.64 g， 0.02 mol)、 四 (三苯基膦)钯 (1.15 g， 1 mmol)和碳酸钠 (4.24 g， 0.04 mol)加入到 60 mLl ,4-二氧六环和 10 mL水中， 加毕加热回流 5小时， TLC监测至原料反应完 全， 过滤， 滤饼用乙酸乙酯洗涤， 滤液减压浓缩后柱层析得到标题产物 3'-硝基 -2'- 甲氧基 -联苯 -4-甲醛 32a(4.1 g， 黄色固体)， 产率： 80.4 %。 第二步 4-formylbenzeneboronic acid (3.0 g, 0.02 mol), 1-bromo-2-methoxy-3-nitrobenzene lc (4.64 g, 0.02 mol), tetrakis(triphenylphosphine)palladium at room temperature (1.15 g, 1 mmol) and sodium carbonate (4.24 g, 0.04 mol) were added to 60 mL of 1,2-dioxane and 10 mL of water, heated and refluxed for 5 hours, monitored by TLC until the reaction of the starting material was complete, filtered, filtered The cake was washed with ethyl acetate, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjj %. Second step
2-(2'-甲氧基 - 3'-硝基-联苯- 4-基) -4,5-二氢- 1H-咪唑 冰浴下， 将 3'-硝基 -2'-甲氧基 -联苯 - 4-甲醛 32a(4.0 g， 15.5 mmol)加入到 40 mL 二氯甲垸中， 搅拌至溶解后加入 1 ,2-二氨基乙垸 (981 mg， 16.3 mmol), 继续搅拌 0.5小时， 加入 1 -溴-吡咯烷 -2,5-二酮 (2.91 g， 16.33 mmol), 加毕撤去冰浴， 室温搅 拌过夜， TLC监测至原料反应完全，反应液减压浓缩后经柱层析得到标题产物 2-(2'- 甲氧基 -3'-硝基 -联苯 -4-基) -4，5-二氢- 1H-咪唑 32b(4.0 g， 黄色固体)， 产率： 86.9 %。 MS m/z (ESI): 298.1 [M+ 1] 2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole, 3'-nitro-2'-methoxy Base-biphenyl-4-formaldehyde 32a (4.0 g, 15.5 mmol) was added to 40 mL of dichloromethane, stirred until dissolved, and 1,2-diaminoacetamidine (981 mg, 16.3 mmol) was added, stirring was continued 0.5 Add 1 -bromo-pyrrolidine-2,5-dione (2.91 g, 16.33 mmol), remove the ice bath after stirring, stir at room temperature overnight, TLC monitor until the reaction of the starting material is complete, and the reaction mixture is concentrated under reduced pressure. The title product 2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32b (4.0 g, yellow solid) was obtained. 86.9 %. MS m/z (ESI): 298.1 [M+ 1]
1丽 MR(400MHz, OMSO-d6): δ 8.11(2H,d,J=8.4), 7.89(l H,dd,Jl=8.0,J2=1.6), 1丽 MR (400MHz, OMSO-d 6 ): δ 8.11 (2H, d, J = 8.4), 7.89 (l H, dd, Jl = 8.0, J2 = 1.6),
7.87(2H,d,J=8.4), 7.79(1 H,m), 7.49(lH,t,J=8.0), 4.04(4H,m), 3.47(3H,s) 第三步 7.87(2H,d,J=8.4), 7.79(1 H,m), 7.49(lH,t,J=8.0), 4.04(4H,m), 3.47(3H,s) Step 3
2-(2'-甲氧基 -3'-氨基 -联苯 -4-基 )-4,5-二氢 -1 H-咪唑 室温下， 将 2-(2'-甲氧基 -3'-硝基 -联苯 -4-基) -4,5-二氢 -1 H-咪唑 32b(1.5 g， 5.05 mmol)加入到 30 mL甲醇中，搅拌溶解后加入甲酸胺 (1.28 g，20.2 mmol)和钯-碳 (200 mg)， 加毕加热回流 1小时， TLC监测至原料反应完全， 反应液自然冷却至室温后 过滤， 滤液减压浓缩得到标题产物 2-(2'-甲氧基 -3'-氨基 -联苯 -4-基) -4,5-二氢 -1H-咪 唑 32c(l . l g， 黄色固体)， 产率： 81.5 %。 2-(2'-methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1 H-imidazole 2-(2'-methoxy-3' at room temperature -Nitro-biphenyl-4-yl)-4,5-dihydro-1 H-imidazole 32b (1.5 g, 5.05 mmol) was added to 30 mL of methanol, stirred and evaporated, and then ethyldiamine (1.28 g, 20.2 And palladium-carbon (200 mg), heated under reflux for 1 hour, TLC was monitored until the starting material was completely reacted, the reaction mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure to give the title product 2-(2'-methoxy- 3'-Amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32c (1. lg, yellow solid), Yield: EtOAc.
MS m/z (ESI): 268.2[M+ 1 ] MS m/z (ESI): 268.2 [M+ 1 ]
'HNM (400MHz, OMSO-d6): δ 8.42(2H,s), 7.96(2H,d,J=8.0), 6.89(1 H,t,J=7.6),
6.75(lH,m), 6.54(lH,dd,Jl=8.0,J2=1.6), 3.80(4H,m), 3.47(3H,s) 第四歩 'HNM (400MHz, OMSO-d 6 ): δ 8.42(2H,s), 7.96(2H,d,J=8.0), 6.89(1 H,t,J=7.6), 6.75(lH,m), 6.54(lH,dd,Jl=8.0,J2=1.6), 3.80(4H,m), 3.47(3H,s)
2-(2'-羟基 -3'-氨基 -联苯 -4-基) -4,5-二氢 - 1 H-咪唑 室温下， 将 2-(2'-甲氧基 - 3'-氨基 -联苯 -4-基:) -4,5-二氢 -1H-咪唑 32c(l .l g， 4.1 mmol)溶解于 50 mL二氯甲垸中， 加入溴化硼的二氯甲垸溶液 (1 N， 16.5 mL), 继 续室温搅拌 4小时， TLC监测至原料反应完全， 用甲醇淬灭反应， 反应液减压浓 缩， 所得固体加入 10 mL乙酸乙酯溶解后搅拌 0.5小时， 过滤， 滤饼用乙酸乙酯洗 涤 (5 mLx2)， 干燥后得到标题产物 2-(2'-羟基 -3'-氨基 -联苯 -4-基 4,5-二氢 -1H-咪唑 32d(900 mg, 灰色固体）， 产率： 89.6%。 2-(2'-hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 2-(2'-methoxy-3'-amino group at room temperature -biphenyl-4-yl:) -4,5-dihydro-1H-imidazole 32c (1.lg, 4.1 mmol) was dissolved in 50 mL of dichloromethane, and a solution of boron bromide in dichloromethane was added. 1 N, 16.5 mL), stirring at room temperature for 4 hours, TLC was monitored until the reaction of the starting material was completed, and the reaction was quenched with methanol. The reaction mixture was concentrated under reduced pressure. The obtained solid was dissolved in 10 mL of ethyl acetate and stirred for 0.5 hour, filtered, filter cake Washed with ethyl acetate (5 mL×2) and dried to give the title product 2-(2'-hydroxy-3'-amino-biphenyl-4-yl 4,5-dihydro-1H-imidazole 32d (900 mg, gray Solid), Yield: 89.6%.
MS m/z (ESI): 254.3[M+ 1] MS m/z (ESI): 254.3 [M+ 1]
'HNMR(400MHz, DMSO-i¾): δ 7.23(2H,m), 7.01(2H,t,J=6.8), 6.65(lH,m), 'HNMR (400MHz, DMSO-i3⁄4): δ 7.23 (2H, m), 7.01 (2H, t, J = 6.8), 6.65 (lH, m),
6.62(lH,dd,J=8.0,J2=l .6), 6.36(lH,t,J=7.6), 4.03(4H,m) 第五步 6.62 (lH, dd, J=8.0, J2=l.6), 6.36 (lH, t, J=7.6), 4.03 (4H, m) Step 5
4-{[4'-(4,5-二氢- 1H-咪唑 -2-基) -2-羟基联苯 -3-基] -肼叉 }-2-茚满 -5-基 -5-甲基 -2,4-二 氢吡唑 -3-酮 4-{[4'-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-indole}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one
冰浴下将 2-(2'-羟基 -3'-氨基 -联苯 -4-基) -4,5-二氢 -1H-咪唑 32d(334 mg, 1.11 mmol)溶解于盐酸 (3.7 mL, 1 mol/L)中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 反应 20分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (214 mg, 1 mmol),用饱和碳酸氢钠溶液调节 pH值至 8，加入 5 mL乙醇，室温反应过夜。 TLC 跟踪至原料消失， 过滤， 所得固体加入到 30 mL水中， 搅拌均匀用浓盐酸调节 pH 值至 4， 有固体析出， 过滤， 所得固体经柱层析得到标题产物 4-{[4'-(4,5-二氢 -1H- 咪唑 -2-基) -2-羟基联苯 -3-基] -肼叉 }-2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 32(145 mg, 红色固体)。 产率： 30.3%。 2-(2'-Hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32d (334 mg, 1.11 mmol) was dissolved in hydrochloric acid (3.7 mL). In 1 mol/L), 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) was added dropwise, and the reaction was carried out for 20 minutes, followed by the addition of 2-indan-5-yl-5-methyl-2,4-dihydropyridinium. Zylin-3-one li (214 mg, 1 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 5 mL of ethanol was added and allowed to react overnight at room temperature. TLC was traced to disappearance of the starting material, filtered, and the obtained solid was added to 30 mL of water, stirred and concentrated to a pH of 4 with concentrated hydrochloric acid. A solid precipitated and filtered, and the obtained solid was subjected to column chromatography to give the title product 4-{[4'-( 4,5-dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-purine}-2-indan-5-yl-5-methyl-2,4-di Hydropyrazol-3-one 32 (145 mg, red solid). Yield: 30.3%.
MS m/z (ESI): 476.9[M-1] MS m/z (ESI): 476.9 [M-1]
'HNMR(400MHz, DMSO-i/6): δ 2.02(m,2H), 2.34(s,3H), 2.87(m,4H), 4.00(s,4H), 6.88(m,lH), 7.18(m,2H), 7.49(m,lH), 7.90(m,5H), 8.18(s,lH) 实施例 33 'HNMR (400MHz, DMSO-i/ 6 ): δ 2.02 (m, 2H), 2.34 (s, 3H), 2.87 (m, 4H), 4.00 (s, 4H), 6.88 (m, lH), 7.18 ( m, 2H), 7.49 (m, lH), 7.90 (m, 5H), 8.18 (s, lH).
5-(2-羟基 -5-甲基 -3-{N'-「3-甲基 -5-氧代 -l-(5,6,7.8-四氢萘 -2-基 ,5-二氢吡唑 -4-亚 基 1-肼基 } -苯 V噻吩 -2-羧酸 5-(2-hydroxy-5-methyl-3-{N'-"3-methyl-5-oxo-l-(5,6,7.8-tetrahydronaphthalen-2-yl, 5-dihydrol Pyrazole-4-ylidene 1-indenyl}-benzene Vthiophene-2-carboxylic acid
MS m/z (ESI): 486.7[M-1] MS m/z (ESI): 486.7 [M-1]
'HNMR(400MHz, DMS。- δ 1.75(m, 4H), 2.3 l(s, 3H), 2.36(s, 3H), 2.73(m, 4H), 7.12(d, J=8.4Hz, 1H), 7.37(s, 1H), 7.56(s, 1H), 7.63(m, 3H), 7.74(d, J=3.6Hz, 1H), 9.77(s, 1H), 13.07(br, 1H), 13.70(s, 1H) 实施例 34 . 'HNMR (400MHz, DMS.- δ 1.75 (m, 4H), 2.3 l (s, 3H), 2.36 (s, 3H), 2.73 (m, 4H), 7.12 (d, J = 8.4 Hz, 1H), 7.37(s, 1H), 7.56(s, 1H), 7.63(m, 3H), 7.74(d, J=3.6Hz, 1H), 9.77(s, 1H), 13.07(br, 1H), 13.70(s , 1H) Example 34.
5-(3-{Ν'-「l-(3,3-二甲基茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基卜肼基 }-2-羟 基 -5-甲基苯) -噻吩 -2-羧酸 5-(3-{Ν'-"l-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-arylene肼基肼}-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid
冰浴下将 5- (3-氨基 -2-羟基 -5-甲基苯基) -噻吩 -2-羧酸氢溴酸盐 24d (366 mg, 5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, ice bath)
1.11 mmol) 溶解于 3.7 mL IN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 反应 20分钟， 再加入 2-(3,3-二甲基茚满 -5-基) -5-甲基- 2,4-二氢吡唑 -3-酮 8i (242 mg, 1 mmol), 用饱和碳酸氢钠溶液调节 pH值至 8， 加入 2 mL乙醇， 撤去 冰浴， 室温反应过夜。 TLC跟踪至原料消失， 过滤， 固体加入到 30 mL水中， 再 用浓盐酸调节 pH=3〜4， 过滤， 固体干燥后得到标题产物 5-(3-{N'-[ 3,3-二甲基
茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 }-2-羟基- 5-甲基苯) -噻吩 -2-羧 酸 34 (308 mg， 红色固体)。 产率： 61.4%。 1.11 mmol) dissolved in 3.7 mL of IN hydrochloric acid, added dropwise 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), reacted for 20 minutes, then added 2-(3,3-dimethylindan-5-yl) -5-Methyl-2,4-dihydropyrazol-3-one 8i (242 mg, 1 mmol), adjusted to pH 8 with saturated sodium bicarbonate solution, 2 mL of ethanol was added, and the ice bath was removed. overnight. TLC was traced to disappearance of the starting material, filtered, and the solid was added to 30 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried to give the title product 5-(3-{N'-[3,3-dimethyl Base Indole-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2-hydroxy-5-methylphenyl)-thiophene- 2-carboxylic acid 34 (308 mg, red solid). Yield: 61.4%.
MS m/z (ESI): 500.8[M-1] MS m/z (ESI): 500.8 [M-1]
'HNMR(400MHz, DMSO-t/6): δ 1 .25(s, 6H), 1.93(m, 2H), 2.36(s, 3H), 2.38(s, 3H), 2.87(t, J=7.2Hz, 2H), 7.27(d, J=8.8Hz, IH), 7.40(d, J=1.6Hz, IH), 7.53(d, J=1.2Hz, IH): 7.65(m, I H), 7.71(m, 2H), 7.74(d, J=4.0Hz, IH), 9.82(br, IH), 13.06(s, I H), 13.71(br, IH) 实施例 35 'HNMR (400MHz, DMSO-t/6): δ 1.25(s, 6H), 1.93(m, 2H), 2.36(s, 3H), 2.38(s, 3H), 2.87(t, J=7.2 Hz, 2H), 7.27(d, J=8.8Hz, IH), 7.40(d, J=1.6Hz, IH), 7.53(d, J=1.2Hz, IH): 7.65(m, IH), 7.71( m, 2H), 7.74 (d, J = 4.0 Hz, IH), 9.82 (br, IH), 13.06 (s, IH), 13.71 (br, IH) Example 35
5-{3-ΓΝ'-Π-双环「4.2.01辛烷 -1(6).2.4-三烯 -3-基 -3-甲基- 5-氧代 -1,5-二氢吡唑 -4-亚 基) -肼基 1-2-羟基 -5-甲基苯 } -噻吩 -2-羧酸 5-{3-ΓΝ'-Π-bicyclic "4.2.01 Octane-1(6).2.4-trien-3-yl-3-methyl- 5-oxo-1,5-dihydropyrazole -4-subunit)-mercapto1-2-hydroxy-5-methylbenzene}-thiophene-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基 -5-甲基苯基) -噻吩 -2-羧酸氢溴酸盐 24d (366 mg, 1.11 mmol) 溶解于 3.7 mL IN盐酸中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 反应 20分钟， 再加入 2-双环 [4.2.0]辛烷 -1 (6),2,4-三烯 -3-基 -5-甲基 -2,4-二 氢吡唑 -3-酮 5d (200 mg, 1 mmol),用饱和碳酸氢钠溶液调节 pH值至 8，加入 2 mL 乙醇，撤去冰浴，室温反应 5小时。 TLC跟踪至原料消失，过滤，固体加入到 30 mL 水中， 再用浓盐酸调节 pH=3〜4， 过滤， 滤饼用 6 mL二氯甲垸洗涤后干燥得到标 题产物 5-{3-[Ν'-(1-双环 [4.2.0]辛垸 -1(6),2，4-三烯 -3-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 ]-2-羟基 -5-甲基苯 噻吩 -2-羧酸 35 (306 mg,红色固体)。产率： 66.5%。 MS m/z (ESI): 459.2[M-1] Dissolve 5-(3-amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) in 3.7 mL of IN hydrochloric acid under ice bath, drop Add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) for 20 minutes, then add 2-bicyclo[4.2.0]octane-1 (6), 2,4-trien-3-yl-5- Methyl-2,4-dihydropyrazol-3-one 5d (200 mg, 1 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, 2 mL ethanol was added, and the ice bath was removed and allowed to react at room temperature for 5 hours. TLC was traced until the starting material disappeared, filtered, and the solid was added to 30 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{3-[Ν '-(1-bicyclo[4.2.0]octyl-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4 -ylidene-indolyl]-2-hydroxy-5-methylphenylthiophene-2-carboxylic acid 35 (306 mg, red solid). Yield: 66.5%. MS m/z (ESI): 459.2 [M-1]
'HNMR(400MHz, DMSO-ί/ό): δ 2.33(s, 3H), 2.36(s, 3H), 3.16(m, 4H), 7.16(d, 'HNMR (400MHz, DMSO-ί/ό): δ 2.33(s, 3H), 2.36(s, 3H), 3.16(m, 4H), 7.16(d,
J=8.0Hz, IH), 7.38(s, IH), 7.49(s， IH), 7.62(m, 2H), 7.73(m, 2H) 实施例 36 J = 8.0 Hz, IH), 7.38 (s, IH), 7.49 (s, IH), 7.62 (m, 2H), 7.73 (m, 2H) Example 36
5-(2-羟基 -3-W'-「3-甲基 -5-氧代 -l-(5,6,7，8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基卜肼 基 苯 V噻吩 -2-羧酸
5-(2-hydroxy-3-W'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyridyl Azole-4-ylidenebenyl V thiophene-2-carboxylic acid
MS m/z (ESI): 472.8[M-1] MS m/z (ESI): 472.8 [M-1]
'HNMR(400MHz, DMSO-i/6): δ 1.74(m, 4H), 2.30(s, 3H), 2.73(m, 4H), 7.12(d, J=8.0Hz, 1H), 7.17(m, 1H), 7.53(d, J=7.6Hz, 1H), 7.62(m, 3H), 7.67(d, J=8.0Hz, 1H), 7.74(d, J=4.0Hz, 1H) 实施例 37 'HNMR (400MHz, DMSO-i/6): δ 1.74 (m, 4H), 2.30 (s, 3H), 2.73 (m, 4H), 7.12 (d, J = 8.0 Hz, 1H), 7.17 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.62 (m, 3H), 7.67 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H) Example 37
5-{3-fN'-(l-双环「4.2.01辛垸 -1 (6),2,4-三烯 -3-基 -3-甲基- 5-氧代 -1,5-二氢吡唑 -4-亚 基) -肼基 1-2-羟基苯 塞吩 -2-羧酸 5-{3-fN'-(l-bicyclic "4.2.01 垸-1 (6), 2,4-trien-3-yl-3-methyl- 5-oxo-1,5-di Hydropyrazol-4-ylidene)-indenyl 1-2-hydroxybensote-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c (298 mg, 0.94 mmol) 溶解于 3.1 mL盐酸 (IN)中， 滴加入 1.3 mL亚硝酸钠溶液 (72 mg, 1.04 mmol), 搅拌 20分钟， 再加入 2-双环 [4.2.0]辛垸 -1(6),2,4-三烯 -3-基 -5-甲基 -2,4-二氢吡唑 -3-酮 5d (170 mg, 0.85 mmol),用饱和碳酸氢钠溶液调节 pH值至 8，用 2 mL乙醇淬灭气泡，
升至室温反应 3小时。 TLC跟踪至原料消失， 过滤出固体， 固体中加入 30 mL水， 用浓盐酸调 pH = 3〜4， 过滤， 固体干燥后经柱层析得到标题产物 5-{3-[N'-G -双环 [4.2.0]辛烷 -1(6),2,4-三烯 -3-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 ]-2-羟基 苯 噻吩 -2-羧酸 37 (57 mg， 红色固体 )。 产率： 15.01%。 5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (298 mg, 0.94 mmol) was dissolved in 3.1 mL hydrochloric acid (IN) and added dropwise to a solution of 1.3 mL. Sodium nitrite solution (72 mg, 1.04 mmol), stirred for 20 minutes, then added 2-bicyclo[4.2.0]octyl-1(6), 2,4-trien-3-yl-5-methyl- 2,4-Dihydropyrazol-3-one 5d (170 mg, 0.85 mmol), adjusted to pH 8 with saturated sodium bicarbonate solution and quenched with 2 mL of ethanol. The reaction was allowed to rise to room temperature for 3 hours. TLC traced to the disappearance of the starting material, the solid was filtered out, 30 mL of water was added to the solid, pH was adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, and dried, and then subjected to column chromatography to give the title product 5-{3-[N'-G- Bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) Mercapto]-2-hydroxyphenylthiophene-2-carboxylic acid 37 (57 mg, red solid). Yield: 15.01%.
MS i-n/z (ESl): 444.5 [M-l ] MS i-n/z (ESl): 444.5 [M-l ]
'HNMR(400MHz, DMSO- 6): δ 2.31(s, 3H), 3.15(m, 4H), 7.15(m, 2H), 7.54(d, J=7.6Hz, 1H), 7.63(m, 2H), 7.67(d, J=7.6Hz, 1H), 7.73(m, 2H) 实施例 38 'HNMR (400MHz, DMSO-6): δ 2.31(s, 3H), 3.15(m, 4H), 7.15(m, 2H), 7.54(d, J=7.6Hz, 1H), 7.63(m, 2H) , 7.67 (d, J = 7.6 Hz, 1H), 7.73 (m, 2H) Example 38
2'-羟基 -3'-{Ν'-Γ3-甲基小(3-甲基茚满 -5-基) -5-氧代 -1 ,5-二氢吡唑 -4-亚基卜肼基 } -联 2'-Hydroxy-3'-{Ν'-Γ3-methyl small (3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-indolyl} -Link
38 38
第一步 First step
6-溴 -茚满 -1-酮 6-bromo-indan-1-one
将 3-(4-溴苯基) -丙酸 38a (20.6 g， 90 mmol, ABCR) 加入 250 mL单口烧瓶中， 真空干燥 20分钟后加入 110 mL重蒸过的二氯甲垸， 氮气保护， 搅拌下加入氯化 亚砜 (20 mL, 276 mmol), 加热回流过夜。 减压下除去大部分溶剂， 加入 100 mL 二氯甲垸， 搅拌下分批加入氯化铝 (24.5 g， 25.8 mmol), 有大量气体放出， 升温回 流反应过夜。 将反应液倒入 200g碎冰中， 析出大量固体， 用硅胶过滤， 分液， 水 相用 30 mL二氯甲垸萃取， 合并的有机相用无水硫酸钠干燥， 减压浓缩， 得到标 题产物 6-溴-茚满小酮 38b (18.34 g， 黄色固体)。 产率： 96.6%。 3-(4-Bromophenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) was added to a 250 mL single-necked flask and dried in vacuo for 20 min. Thionyl chloride (20 mL, 276 mmol) was added with stirring and heated to reflux overnight. Most of the solvent was removed under reduced pressure, and 100 mL of dichloromethane was added, and aluminum chloride (24.5 g, 25.8 mmol) was added portionwise with stirring, and a large amount of gas was released, and the reaction was refluxed overnight. The reaction mixture was poured into 200 g of crushed ice, and a large amount of solid was precipitated, which was purified by silica gel chromatography. 6-Bromo-indanone 38b (18.34 g, yellow solid). Yield: 96.6%.
MS m/z (ESI): 210[M-1 ]
第二步 MS m/z (ESI): 210 [M-1 ] Second step
6-溴小亚甲基-茚满 6-bromomethylene-indane
将甲基 =苯基溴化膦 (4.56 g， 12.76 mmol)溶解于 25 mL四氢呋喃中，一次性加 入叔丁醇钾 (1.5g, 13.4 mmol), 加入完毕后室温下搅拌 35分钟备用。 The methyl group = phenylphosphonium bromide (4.56 g, 12.76 mmol) was dissolved in 25 mL of tetrahydrofuran, and potassium t-butoxide (1.5 g, 13.4 mmol) was added in one portion, and the mixture was stirred at room temperature for 35 minutes.
将 6-溴 -茚满 -1 -酮 38b (898 mg, 4.25 mmol) 溶解于 5 mL四氢呋喃中， 搅拌下 滴加入上述的溶液中， 所得溶液在室温下搅拌 1小时， 加入 25 mL水淬灭反应。 用二氯甲垸萃取 (25 mLx4) 反应液， 合并的有机相用饱和食盐水 (10 mL )洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离 纯化，得到标题产物 6-溴- 1-亚甲基 -茚满 38c (830 mg,黄色油状液体)。产率： 93.4%。 MS nVz (ESl): 208[M-1] 第三歩 6-Bromo-indan-1 -one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran, and the solution was added dropwise with stirring. The resulting solution was stirred at room temperature for 1 hour and quenched with 25 mL of water. reaction. The mixture was extracted with chloroform (25 mL EtOAc). EtOAc (EtOAc m. Separation and purification gave the title product 6-bromo-1-methylene-indane 38c (830 mg,yield of yellow oil). Yield: 93.4%. MS nVz (ESl): 208 [M-1] third
6-溴 - 甲基茚满 6-bromo-methylindane
将 6-溴小亚甲基茚满 38c(4.91 g， 23.5 mmol)溶解于乙酸乙酯中，加入钯-碳 (0.98 g), 在氢气氛下室温反应 4小时， TLC跟踪至原料消失， 反应液过滤， 滤液减压 浓缩后柱层析得到标题产物 6-溴 -1-甲基茚满 38d(3.11g， 无色油状液体)， 产率： 62.7%。 6-Bromomethylene indan 38c (4.91 g, 23.5 mmol) was dissolved in ethyl acetate, palladium-carbon (0.98 g) was added, and the reaction was carried out for 4 hours at room temperature under a hydrogen atmosphere, and the TLC was traced until the starting material disappeared. The filtrate was filtered, and the filtrate was evaporated tolululululululululululululululululululululululululululululu
MS m/z (ESI): 209.8 [M-1] 第四步 MS m/z (ESI): 209.8 [M-1] Step 4
1-(3-甲基茚满 -5-基)肼 -1,2-二甲酸二叔丁酯 1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-tert-butyl ester
氩气氛下， 将正丁基锂 (8.6 mL, 13.76 mmol) 加入到三口烧瓶中， 在干冰-丙 酮浴冷却下加入 8 mL四氢呋喃中， 搅拌下加入 6-溴 -1-甲基茚满 38d (1.32 g， 6.26 mmol),所得溶液在干冰-丙酮浴下反应 2小时， 滴加偶氮二甲酸二叔丁酯 G .87 g， 8.14 mmol) 的 10 mL四氢呋喃溶液， 继续搅拌 30分钟， 撤去冰浴， 升温至室温， 搅拌 20小时反应完毕。 将反应液中加入 20 mL饱和氯化胺淬灭反应， 用乙酸乙酯 萃取 (25 mLx3;i反应液， 合并的有机相用饱和食盐水 (10 mL><2)洗涤， 无水硫酸钠干 燥， 过滤， 滤液减压下浓缩， 残留物通过硅胶柱层析得到标题产物 1-(3-甲基茚满 -5-基)肼 -1,2-二甲酸二叔丁酯 38e (1.05 g， 黄色油状液体)。 产率： 46.7%。 Under an argon atmosphere, n-butyllithium (8.6 mL, 13.76 mmol) was added to a three-necked flask, and added to 8 mL of tetrahydrofuran under a dry ice-acetone bath, and 6-bromo-1-methylindane 38d was added with stirring. 1.32 g, 6.26 mmol), the obtained solution was reacted in a dry ice-acetone bath for 2 hours, and a solution of di-tert-butyl azodicarboxylate G.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran was added dropwise, stirring was continued for 30 minutes, and ice was removed. The mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was quenched by the addition of 20 mL of EtOAc. EtOAc (EtOAc (EtOAc) After filtration, the filtrate was concentrated under reduced pressure. Yellow oily liquid). Yield: 46.7%.
MS m/z (ESI): 362.6[M+1] 第五步 MS m/z (ESI): 362.6 [M+1] Step 5
5-甲基 -2-P-甲基茚满 -5-基) -2,4-二氢吡唑 -3-酮 5-methyl-2-P-methylindan-5-yl)-2,4-dihydropyrazole-3-one
将 1-(3-甲基茚满 -5-基)肼 -1,2-二甲酸二叔丁酯 38e (1.05 g， 2.9 mmol)溶解于 16 mL乙醇和水混合溶剂 (V:V=5:3)中， 搅拌下依次加入乙酰乙酸乙酯 (0.377 mL， 2.9 mmol)和 1.45 mL 6N盐酸， 氮气保护下， 加热回流反应 1.5小时反应完毕。 冷却至
室温， 将反应液在减压下浓缩， 除去乙醇， 水相用二氯甲垸萃取 (15 mLx3)， 合并 的¾"机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 残留物通过硅胶柱层析得到 标题产物 5-甲基 -2-(3-甲基茚满 -5-基) -2,4-二氢吡唑 -3-酮 38f (103 mg， 黄色油状液 体）。 产率： 15.6%。 Dissolve 1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-tert-butyl ester 38e (1.05 g, 2.9 mmol) in 16 mL of a mixed solvent of ethanol and water (V:V=5) In 3), ethyl acetoacetate (0.377 mL, 2.9 mmol) and 1.45 mL of 6N hydrochloric acid were successively added under stirring, and the reaction was heated under reflux for 1.5 hours under nitrogen atmosphere. Cool down to The reaction mixture was concentrated under reduced pressure at room temperature. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Silica gel column chromatography gave the title product 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f (103 mg, yellow oily). Rate: 15.6%.
MS m/z (ESI): 229.3[M+1] 第六步 MS m/z (ESI): 229.3 [M+1] Step 6
2'-羟基 -3'-{N'-[3-甲基 -l-(3-甲基茚满 -5-基) -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼 基} -联苯 -3-羧酸 2'-Hydroxy-3'-{N'-[3-methyl-l-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-arylene -] fluorenyl}-biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (344 mg, 1.11 mmol)溶解于 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (344 mg, 1.11 mmol) was dissolved in an ice bath
3.7 mL盐酸 (IN)中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 再加入 5-甲 基 -2-(3-甲基茚满 -5-基) -2,4-二氢吡唑 -3-酮 38f (228 mg, 1 mmol), 用饱和碳酸氢钠 溶液将反应液 pH调至 8， 加入 2 mL乙醇， 升至室温过夜。 TLC跟踪至原料消失， 过滤出固体， 固体中加入 30 mL水， 用浓盐酸调 pH = 3〜4， 过滤， 固体干燥后加 入 10 mL二氯甲垸和甲醇的混合溶液 (V:V=50: 1)， 加毕搅拌 1小时， 过滤， 滤饼用 二氯甲垸洗涤 (2 mLx3),干燥后得到标题产物 2'-羟基 -3'-{Ν'- [3-甲基 -1-(3-甲基茚满 -5-基) -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 联苯 -3-羧酸 38(300 mg， 黄色固体)。 产 率： 64.1%。 Add 1.7 mL of hydrochloric acid (IN), add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), and add 5-methyl-2-(3-methylindan-5-yl)-2,4- Dihydropyrazol-3-one 38f (228 mg, 1 mmol), the pH of the mixture was adjusted to 8 with saturated sodium bicarbonate solution, and then, 2 TLC traced to the disappearance of the starting material, the solid was filtered out, 30 mL of water was added to the solid, pH = 3~4 was adjusted with concentrated hydrochloric acid, filtered, and the solid was dried, and then 10 mL of a mixed solution of dichloromethane and methanol was added (V: V = 50). : 1), stirring for 1 hour, filtering, filter cake washed with dichloromethane (2 mL x 3), dried to give the title product 2'-hydroxy-3'-{Ν'- [3-methyl-1- (3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-ylidene]-mercaptobiphenyl-3-carboxylic acid 38 (300 mg, yellow solid) . Yield: 64.1%.
MS m/z (ESI): 466.9[M-1] MS m/z (ESI): 466.9 [M-1]
'HNMR(400MHz, DMSO-t/6): δ 1.25(m, 3H), l ,58(m, IH), 2.30(m, IH), 2.33(s, 3H), 2.80(m, 2H), 3.19(m, IH), 7.13(m, 2H), 7.26(d, J=8.0Hz, IH), 7.62(t, J=7.6Hz, IH), 7.69(m, 3H), 7.80(d, J=7.6Hz, IH), 7.97(d, J=7.6Hz, IH), 8.43(s, IH), 9.69(br, IH), 13.06(s, IH), 13.76(s, IH) 实施例 39 'HNMR (400MHz, DMSO-t/6): δ 1.25 (m, 3H), l, 58 (m, IH), 2.30 (m, IH), 2.33 (s, 3H), 2.80 (m, 2H), 3.19(m, IH), 7.13(m, 2H), 7.26(d, J=8.0Hz, IH), 7.62(t, J=7.6Hz, IH), 7.69(m, 3H), 7.80(d, J = 7.6 Hz, IH), 7.97 (d, J = 7.6 Hz, IH), 8.43 (s, IH), 9.69 (br, IH), 13.06 (s, IH), 13.76 (s, IH) Example 39
2'-羟基 -5'-甲基 -3'-{N'-「3-甲基 -l-(3-甲基茚满 -5-基) -5-氧代 -1.5-二氢吡唑 -4-亚基卜肼 基} -联苯 -3-羧酸 2'-Hydroxy-5'-methyl-3'-{N'-"3-methyl-l-(3-methylindan-5-yl)-5-oxo-1.5-dihydropyrazole -4-indolyl}-biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 llf (360 mg, 1.11 mmol)
溶解于 3.7 mL盐酸 (IN)中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 搅拌 20分钟， 再加入 5-甲基 -2-(3-甲基茚满 -5-基) -2,4-二氢吡唑 -3-酮 38f (228 mg, 1.0 mmol), 用饱和碳酸氢钠溶液将反应液 pH调至 8， 加入 2 mL乙醇， 升至室温反应 过夜。 TLC跟踪至原料消失， 过滤出固体， 用 30 mL水溶解， 搅拌均匀， 用浓盐 酸调 pH = 3〜4，过滤， 固体干燥后加入 10 mL二氯甲垸搅拌 1小时，过滤出固体， 固体干燥后得到标题产物 2'-轻基 -5'-甲基 -3'-{N'-[3-甲基 -1-(3-甲基茚满 -5-基 5-氧 代 -1 ,5-二氢吡唑 -4-亚基] -肼基 联苯 -3-羧酸 39(240 mg， 红色固体)。 产率： 49.8%。 MS m/z (ESI): 480.9[M-1] 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride llf (360 mg, 1.11 mmol) under ice bath Dissolve in 3.7 mL of hydrochloric acid (IN), add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), stir for 20 minutes, then add 5-methyl-2-(3-methylindan-5-yl) -2,4-Dihydropyrazol-3-one 38f (228 mg, 1.0 mmol). The pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 TLC traced to the disappearance of the starting material, filtered solids, dissolved in 30 mL of water, stirred evenly, adjusted to pH = 3~4 with concentrated hydrochloric acid, filtered, solid dried, then added 10 mL of dichloromethane, stirred for 1 hour, filtered solid, solid After drying, the title product 2'-light- 5'-methyl-3'-{N'-[3-methyl-1-(3-methylindan-5-yl 5-oxo-1, 5-Dihydropyrazole-4-ylidene]-mercaptobiphenyl-3-carboxylic acid 39 (240 mg, red solid). Yield: 49.8%. MS m/z (ESI): 480.9 [M-1 ]
'HNMR(400MHz, DMSO- 6): δ 1.29(m, 3H), 1.56(m, IH), 2.28(m, IH), 2.34(s, 3H), 2.36(s, 3H), 2.80(m, 2H), 3.18(m, IH), 7.00(s, IH), 7.27(d, J=8.0Hz, IH), 7.54(s, IH), 7.61 (t, J=7.6Hz, IH), 7.70(m, 2H), 7.80(d, J=8.0Hz, IH), 7.95(d, J=7.6Hz， IH), 8.14(d, J=4.4Hz, IH), 9.40(br, IH), 13.03(s, IH), 13.76(s, IH) 实施例 40 'HNMR (400MHz, DMSO-6): δ 1.29 (m, 3H), 1.56 (m, IH), 2.28 (m, IH), 2.34 (s, 3H), 2.36 (s, 3H), 2.80 (m, 2H), 3.18(m, IH), 7.00(s, IH), 7.27(d, J=8.0Hz, IH), 7.54(s, IH), 7.61 (t, J=7.6Hz, IH), 7.70( m, 2H), 7.80 (d, J = 8.0 Hz, IH), 7.95 (d, J = 7.6 Hz, IH), 8.14 (d, J = 4.4 Hz, IH), 9.40 (br, IH), 13.03 ( s, IH), 13.76(s, IH) Example 40
5-(2-羟基 -3-ίΝ'-「3-甲基 -l-(3-甲基茚满 -5-基)- 5-氧代 -1.5-二氢吡唑 -4-亚基 肼基 苯) -噻吩 -2-羧酸 5-(2-hydroxy-3-ίΝ'-"3-methyl-l-(3-methylindan-5-yl)- 5-oxo-1.5-dihydropyrazole-4-ylidene Thiophene-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c (351 mg, 1.11 mmol) 溶解于 3.7 mL盐酸 (IN)中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 搅拌 20 分钟， 再加入 5-甲基 -2-(3-甲基茚满 -5-基) -2,4-二氢吡唑- 3-酮 38f (228 mg, 1 mmol), 用饱和碳酸氢钠溶液调节 pH值至 8， 用 2 mL乙醇淬灭气泡， 升至室温反 应 3小时。 TLC跟踪至原料消失， 过滤出固体， 固体中加入 30 mL水， 用浓盐酸 调 pH = 3〜4， 过滤， 固体干燥后经柱层析得到标题产物 5-(2-羟基 -3-{N'-[3-甲基 -1-(3-甲基茚满 -5-基) -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 苯) -噻吩 -2-羧酸 40 (90 mg, 红色固体)。 产率： 19.0%。 5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (351 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (IN), and 1.5 mL was added dropwise. Sodium nitrite solution (85 mg, 1.22 mmol), stirred for 20 minutes, then added 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazole-3-one 38f (228 mg, 1 mmol), the pH was adjusted to 8 with a saturated sodium bicarbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature for 3 hours. TLC was traced to disappearance of the starting material, the solid was filtered, 30 mL of water was added to the solid, pH was adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, and dried to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-ylidene]-mercaptophenyl)-thiophene- 2-carboxylic acid 40 (90 mg, red solid). Yield: 19.0%.
MS m/z (ESI): 472.8[M-1] MS m/z (ESI): 472.8 [M-1]
'HNMR(400MHz, DMSO- 6): δ 1.26(m, 3H), 1.58(m, IH), 2.30(m, IH), 2.32(s, 3H), 2.82(m, 2H), 3.18(m, IH), 7.16(t, J=8.0Hz, IH), 7.27(d, J=8.0Hz, 1H)， 7.54(d, J=7.6Hz, IH), 7.70(m, 5H), 10.09(br, IH), 13.71(br, IH)
买施例 41 'HNMR (400MHz, DMSO-6): δ 1.26 (m, 3H), 1.58 (m, IH), 2.30 (m, IH), 2.32 (s, 3H), 2.82 (m, 2H), 3.18 (m, IH), 7.16(t, J=8.0Hz, IH), 7.27(d, J=8.0Hz, 1H), 7.54(d, J=7.6Hz, IH), 7.70(m, 5H), 10.09(br, IH), 13.71(br, IH) Buying example 41
3'-{Ν'-Π-(3-乙基-茚满- 5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基 1-肼基 }-2'-羟基联 3'- {Ν '-Π-(3-ethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 1-indenyl }-2'-hydroxyl association
苯 -3-羧酸 Benzene-3-carboxylic acid
第一步 First step
6-溴小亚乙基 -茚满 6-bromoethylidene
室温下， 将乙基三苯基溴化膦 (14.5 g, 39.1 mmol)溶解于 75 mL四氢呋喃中， 加入叔丁醇钾 (5.29 g, 47.3 mmol)，加毕室温搅拌 1小时。将 6-溴 -茚满 -1-酮 38b (3.39 g， 18.6 mmol) 溶解于 25 mL四氢呋喃中， 搅拌下滴加入上述的溶液中， 加毕继续 于室温下搅拌 1小时。 TLC监测至原料反应完全， 向反应液中加入 150 mL水淬灭 反应， 用二氯甲垸萃取反应液 (50 mLx4)， 合并有机相， 有机相用饱和食盐水洗涤 (45 mLx2), 无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题 产物 6-溴小亚乙基 -茚满 41a(3.07 g， 黄色油状液体)， 产率： 74%。 Ethyltriphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran, and potassium t-butoxide (5.29 g, 47.3 mmol) was added and stirred at room temperature for 1 hour. 6-Bromo-indan-1-one 38b (3.39 g, 18.6 mmol) was dissolved in 25 mL of tetrahydrofuran, and the solution was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched by the addition of 150 mL of water. The reaction mixture was extracted with dichloromethane (50 mL×4). The organic phase was combined and washed with brine (45 mL×2) The organic layer was dried over sodium sulfate, filtered and evaporated, evaporated, evaporated, evaporated, evaporated.
MS m/z (ESI): 221.8[M-1] 第二步 MS m/z (ESI): 221.8 [M-1] Step 2
6-溴 -1-乙基 -茚满 6-bromo-1-ethyl-indane
室温下， 将 6-溴 -1-亚乙基 -茚满 41a(3.07 g， 13.7 mmol)溶解于 80 mL乙酸乙酉旨 中， 加入钯-碳 (0.61 g)， 于氢化仪中在 3个大气压下用氢气氢化， 室温反应 5小时 后， TLC 监测原料反应完全， 反应液过滤除去钯 -碳， 滤饼用乙酸乙酯洗涤 (10 mLx3), 滤液减压浓缩后柱层析， 得到标题产物 6-溴 -1-乙基 -茚满 41b(2.75 g， 浅 黄色液体)， 产率： 88.7%。 6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate at room temperature, and palladium-carbon (0.61 g) was added in a hydrogenation apparatus at 3 atm. After hydrogenation with hydrogen, the mixture was reacted for 5 hours at room temperature, and the reaction of the material was monitored by TLC. The reaction mixture was filtered to remove palladium-carbon, and the filter cake was washed with ethyl acetate (10 mL×3), and the filtrate was concentrated under reduced pressure to give the title product 6 -Bromo-1-ethyl-indan 41b (2.75 g, pale yellow liquid), Yield: 88.7%.
MS m/z (ESI): 224[M-1] 第三步
1 -(3-乙基 -2，3-二氢-】 H-茚满 -5-基) -1 -叔丁氧羰基 -2-叔丁氧羰基-肼 氩气氛下， 将 6-溴 -1 -乙基 -茚满 41b(2.52 g， 1 1 .2 mmol)溶解于 15 mL四氢呋喃 中， 滴加到干冰-丙酮浴浴冷却的叔丁基锂的环已垸溶液中 (18.1 mL， 1 .3 N) , 加毕 继续于干冰-丙酮浴中搅拌 2小时。 将偶氮二甲酸二叔丁酯溶解于 15 mL四氢呋喃 中， 滴加到上述反应液中， 加毕继续于干冰-丙酮浴中搅拌 0.5小时， 撤去干冰-丙 酮浴， 反应液自然升至室温后搅拌 18小时， TLC监测原料反应完全， 向反应液中 加入 25 mL氯化氨饱和溶液淬灭反应， 用乙酸乙酯 (30 mL <3)萃取反应液， 合并有 机相， 用无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产 物 1 -(3-乙基 -2,3-二氢- 1 H-茚满 -5-基) - 1-叔丁氧羰基 -2-叔丁氧羰基-肼 41c(3.43 g，棕 黄色油状液体)， 产率： 81.5 %。 第四步 MS m/z (ESI): 224 [M-1] Step 3 1-(3-ethyl-2,3-dihydro-)H-indan-5-yl)-1 -tert-butoxycarbonyl-2-tert-butoxycarbonyl-argon under argon atmosphere, 6-bromo- 1 -Ethyl-indan 41b (2.52 g, 11.2 mmol) was dissolved in 15 mL of tetrahydrofuran and added dropwise to a solution of tert-butyllithium in a dry ice-acetone bath (18.1 mL, 1 .3 N), the addition was continued in a dry ice-acetone bath for 2 hours. The di-tert-butyl azodicarboxylate was dissolved in 15 mL of tetrahydrofuran, added dropwise to the above reaction solution, and the mixture was further stirred in a dry ice-acetone bath for 0.5 hour, and the dry ice-acetone bath was removed, and the reaction solution was naturally warmed to room temperature. After stirring for 18 hours, the reaction of the starting material was completely monitored by TLC. To the reaction mixture was added 25 mL of a saturated solution of ammonium chloride to quench the reaction. The mixture was extracted with ethyl acetate (30 mL <3), and the organic phases were combined and dried over anhydrous sodium sulfate The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure and then purified to give the title product 1-(3-ethyl-2,3-dihydro-1H-indane-5-yl)-1-tert-butoxycarbonyl- 2-tert-Butoxycarbonyl-indole 41c (3.43 g, brownish yellow oily). Yield: mp. the fourth step
2-0乙基 -茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 室温下， 将 1-(3-乙基 -2,3-二氢 -1H-茚满 -5-基) - 1 -叔丁氧羰基- 2-叔丁氧羰基-肼 41 c(3.43 g, 9.1 mmol)溶解于 50 mL乙醇和水的混合溶剂中 (V:V=3:2)， 加入 3-氧代 -丁酸乙酯 (1.18 g， 9.1 mmol)和 4.55 mL盐酸 (6N；)， 加毕， 反应液回流 1小时， TLC 监测原料反应完全， 反应液减压除去乙醇， 再用二氯甲垸萃取 (15 mLx3)， 合并有 机相， 有机相用无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到 标题产物 2-(3-乙基 -茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 41d(0.712 g， 黄色油状液 体）， 产率： 39.8 %。 2-0 ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one at room temperature, 1-(3-ethyl-2,3-dihydro- 1H-indan-5-yl)-1 -tert-butoxycarbonyl-2-tert-butoxycarbonyl-indole 41 c (3.43 g, 9.1 mmol) was dissolved in 50 mL of a mixed solvent of ethanol and water (V:V= 3:2), 3-oxo-butyric acid ethyl ester (1.18 g, 9.1 mmol) and 4.55 mL hydrochloric acid (6N;) were added. After the addition, the reaction solution was refluxed for 1 hour, and the reaction of the starting material was completely monitored by TLC. The ethanol was removed, and extracted with dichloromethane (15 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. Base-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d (0.712 g, yellow oily). Yield: 39.8 %.
MS m/z (ESI): 243.2[M+ 1] 第五步 MS m/z (ESI): 243.2 [M+ 1] Step 5
3'-{Ν'-[1-(3-乙基 -茚满 -5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基] -肼基 }-2'-羟基联 苯 -3-羧酸 3'-{Ν'-[1-(3-ethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indole }}-2'-hydroxybiphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基联苯基 -3-羧酸氢溴酸盐 If (285 mg, 0.92 mmol)溶解于 3.1 mL盐酸 (IN)中， 滴加入 1.2 mL亚硝酸钠溶液 (70 mg, 1.01 mmol) , 继续搅拌 20 分钟， 加入 2-(3-乙基 -茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 41d (200 mg, 0.83 mmol) ,用饱和碳酸氢钠溶液将反应液 pH调至 8，加入 2 mL乙醇，升至室温过夜。 TLC跟踪至原料消失， 过滤， 固体加入 20 mL水， 用浓盐酸调节 pH值至 3〜4， 过滤出固体， 固体干燥后得到标题产物 3'-{Ν'-[1 -(3-乙基 -茚满 -5-基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基] -肼基 } -2'-羟基联苯 -3-羧酸 41(145 mg, 红色固体)， 产率- 36.4%。 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide If (285 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (IN) under ice bath, and 1.2 mL of sodium nitrite was added dropwise. Solution (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d ( 200 mg, 0.83 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. TLC was traced to disappearance of the starting material, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{Ν'-[1 -(3-ethyl -indol-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxybiphenyl-3-carboxylic acid 41 (145 mg, red solid), Yield - 36.4%.
MS m/z (ESI): 480.9[M-1 ] MS m/z (ESI): 480.9 [M-1]
'HNMR(400MHz, DMSO-d6): δ 0.95(m, 3H), 1.43(m, 1 H), 1.65(m, 1H), 1.83(m, 1 H), 2.23(m, 1H), 2.34(s, 3H), 2.92(m, 2H), 3.05(m, 1 H), 7.15(s, 2H), 7.27(d, J=8.0Hz, 1H), 7.62(t, J=8.0Hz, 1H)， 7.72(m, 3H), 7.80(d, J=7.6Hz, 1 H)， 7.97(d, J=8.0Hz, 1 H), 8.14(s,
1H), 9.66(s, 1H), 13.04(s, 1H), 13.76(s, 1 H) 实施例 42 'HNMR (400MHz, DMSO-d6): δ 0.95 (m, 3H), 1.43 (m, 1 H), 1.65 (m, 1H), 1.83 (m, 1 H), 2.23 (m, 1H), 2.34 ( s, 3H), 2.92(m, 2H), 3.05(m, 1 H), 7.15(s, 2H), 7.27(d, J=8.0Hz, 1H), 7.62(t, J=8.0Hz, 1H) , 7.72(m, 3H), 7.80(d, J=7.6Hz, 1 H), 7.97(d, J=8.0Hz, 1 H), 8.14(s, 1H), 9.66(s, 1H), 13.04(s, 1H), 13.76(s, 1 H) Example 42
3'-ίΝ'-「1- (3-乙基-茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基 肼基 }-2'-羟基 -5'- 甲基-联苯— 3-羧酸 3'-ίΝ'-"1-(3-ethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene}}- 2'-hydroxy-5'-methyl-biphenyl-3-carboxylic acid
冰浴下将 3'-氨基 -2'-羟基 -5'-甲基联苯基 -3-羧酸盐酸盐 llf (298 mg, 0.92 mmol) 溶解于 3.1 mL盐酸 (IN)中， 滴加入 1.2 mL亚硝酸钠溶液 (70 mg, 1.01 mmol), 继续 搅拌 20分钟， 加入 2-(3-乙基 -茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 41d (200 mg, 0.83 mmol), 用饱和碳酸氢钠溶液将反应液 pH调至 8， 加入 2 mL乙醇， 升至室温 过夜。 TLC跟踪至原料消失，过滤，固体加入 20 mL水，用浓盐酸调节 pH值至 3〜 4， 过滤出固体， 固体干燥后得到标题产物 3'-{Ν'-[1-(3-乙基-茚满- 5-基) -3-甲基 -5- 氧代 -1,5-二氢吡唑 -4-亚基] -肼基 }-2'-羟基- 5'-甲基 -联苯 -3-羧酸 42(290 mg, 红色固 体）， 产率： 70.7%。 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride llf (298 mg, 0.92 mmol) was dissolved in 3.1 mL hydrochloric acid (IN) under ice bath, and added dropwise 1.2 mL of sodium nitrite solution (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazole- 3-ketone 41d (200 mg, 0.83 mmol). The pH of the reaction mixture was adjusted to 8 with saturated sodium hydrogen carbonate solution, and 2 TLC was traced to disappearance of the starting material, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{Ν'-[1-(3-ethyl -Indole-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxy- 5'-methyl-linked Benzene-3-carboxylic acid 42 (290 mg, red solid), Yield: 70.7%.
MS m/z (ESI): 494.9[M-1] MS m/z (ESI): 494.9 [M-1]
'HNMR(400MHz, DMSO-i d): δ 0.95(m, 3H), 1.43(m, 1H), 1.65(m， 1H), 1.83(m, 1H), 2.23(m, 1H), 2.34(s, 3H), 2.92(m, 2H), 3.05(m, 1H), 6.99(s, 1H), 7.26(d, J=8.0Hz, 1H), 7.53(s, 1H), 7.60(t, J=8.0Hz， 1H), 7.68(m, 1H), 7.75(s, 1H), 7.80(d, J=7.6Hz, 1H), 7.96(d, J=7.6Hz, 1H), 8.14(s, 1H)， 9.39(s, 1H), 13.03(s, 1H), 13.76(s, 1H) 实施例 43 'HNMR (400MHz, DMSO-i d): δ 0.95(m, 3H), 1.43(m, 1H), 1.65(m, 1H), 1.83(m, 1H), 2.23(m, 1H), 2.34(s , 3H), 2.92(m, 2H), 3.05(m, 1H), 6.99(s, 1H), 7.26(d, J=8.0Hz, 1H), 7.53(s, 1H), 7.60(t, J= 8.0Hz, 1H), 7.68(m, 1H), 7.75(s, 1H), 7.80(d, J=7.6Hz, 1H), 7.96(d, J=7.6Hz, 1H), 8.14(s, 1H) , 9.39(s, 1H), 13.03(s, 1H), 13.76(s, 1H) Example 43
5— 0-{Ν'— Π-(3，3-二甲基茚满 -5-基) -3-甲基- 5-氧代 -1,5-二氢吡唑 -4-亚基 1-肼基 2-羟 基苯) -呋喃 -2-羧酸 5 — 0- {Ν '- Π-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 1 -mercapto 2-hydroxybenzene)-furan-2-carboxylic acid
MS m/z (ESI): 470.9[M-1] MS m/z (ESI): 470.9 [M-1]
'HNMR(400MHz, DMSO-i/<5): δ 1.26(s, 6H), 1.92(t, J=7.2Hz, 2H), 2.33(s, 3H)， 2.86(t, J=7.2Hz， 2H), 7.15(m, IH), 7.20(m, 2H), 7.37(d, J=3.6Hz, IH), 7.55(d, .1=6.8Hz, IH), 7.71(m, 3H), 9.99(br, IH), 13.15(br, IH), 13.74(br, IH) 实施例 44 'HNMR (400MHz, DMSO-i/<5): δ 1.26(s, 6H), 1.92(t, J=7.2Hz, 2H), 2.33(s, 3H), 2.86(t, J=7.2Hz, 2H ), 7.15(m, IH), 7.20(m, 2H), 7.37(d, J=3.6Hz, IH), 7.55(d, .1=6.8Hz, IH), 7.71(m, 3H), 9.99( Br, IH), 13.15(br, IH), 13.74(br, IH) Example 44
5-(2-羟基 -3-{Ν'-Γ3-甲基小 G-甲基茚满 -5-基) -5-氧代 -1，5-二氢吡唑 -4-亚基 1-肼基 苯) -呋喃 -2-羧酸 5-(2-hydroxy-3-{Ν'-Γ3-methyl small G-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-ylidene 1- Mercaptobenzene)-furan-2-carboxylic acid
38f 9c 38f 9c
冰浴下将 5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 9c (333 mg, 1.1 mmol)溶 解于盐酸 (3.7 mL, 1 mol/L)中， 滴加入 1.5 mL亚硝酸钠溶液 (85 mg, 1.22 mmol), 反 应 20分钟， 再加入 5-甲基 -2-(3-甲基茚满 -5-基) -2,4-二氢吡唑 -3-酮 38c (228mg， 1.0 mmol), 分批加入碳酸氢钠 (1.4 g， 16.67 mmol)和 3 mL乙醇， 室温反应过夜。 TLC 跟踪至原料消失， 过滤， 固体加入 20 mL水， 用浓盐酸调节 pH值至 3〜4， 过滤 出固体， 固体干燥后经柱层析得到标题产物 5-(2-羟基 -3-{N'-[3-甲基 -1-(3-甲基茚满 -5-基) -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 苯) -呋喃 -2-羧酸 44(110 mg, 红色固体)，
产率： 24.0%。 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L). Add 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) dropwise for 20 minutes, then add 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazole 3-ketone 38c (228 mg, 1.0 mmol), sodium bicarbonate (1.4 g, 16.67 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 20 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered, dried and dried to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4-ylidene]-mercaptophenyl)-furan- 2-carboxylic acid 44 (110 mg, red solid), Yield: 24.0%.
MS m/z (ESI): 457.0[M-1 ] MS m/z (ESI): 457.0 [M-1]
'HNMR(400MHz, DMSO- 6): δ 1.25(m, 3H), 1.59(m, 1H), 2.29(m, 1H), 2.33(s, 3H), 2.84(m, 2H), 3.17(m, 1H), 7.14(d, J=3.2Hz, 1H), 7.22(t, J=8.0Hz, 1H), 7.28(d, J=8.0Hz, 1 H), 7.36(d, J=3.2Hz, 1H), 7.55(d, J=8.0Hz, 1H), 7.71(m, 3H)9.96(br, l H)13.75(br, 1H) 实施例 45 'HNMR (400MHz, DMSO-6): δ 1.25 (m, 3H), 1.59 (m, 1H), 2.29 (m, 1H), 2.33 (s, 3H), 2.84 (m, 2H), 3.17 (m, 1H), 7.14(d, J=3.2Hz, 1H), 7.22(t, J=8.0Hz, 1H), 7.28(d, J=8.0Hz, 1 H), 7.36(d, J=3.2Hz, 1H ), 7.55 (d, J = 8.0 Hz, 1H), 7.71 (m, 3H) 9.96 (br, l H) 13.75 (br, 1H) Example 45
5-0-{Ν'-Π— 2-二甲基茚满 -5—基 )— 3—甲基 -5—氧代— 二氢吡唑—4—亚基 I—肼基 }— 2_经 基苯) -呋喃 -2-羧酸 5 -0-{ Ν '- Π — 2 -dimethylindan- 5 -yl)-3-methoxy-5-oxo-dihydropyrazole-4-subunit I-fluorenyl}- 2 _ Mercaptophenyl)-furan-2-carboxylic acid
笛 _ Flute _
6-溴 -2,2-二甲基茚满 -1-酮 6-bromo-2,2-dimethylindan-1-one
将 6-溴 -茚满 -1-酮 38b (6.02 g， 28.5 mmol)和碘甲浣 (4.4 mL， 70 mmol)溶解于 200 mL四氢呋喃 (干燥)中， 室温搅拌 15分钟， 加入氢化钠 (2.73 g, 68.2 mmol), 继续搅拌 2小时， TLC监测至原料反应完全， 反应液中加入 150 mL水， 用乙酸乙 酯萃取 (150 mLx2)， 合并有机相， 有机相用饱和食盐水洗涤， 无水硫酸钠干燥， 过 滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产物 6-溴 -2,2-二甲基茚满 -1-酮 45a(5.36 g, 棕色固体)， 产率： 78.6%。 6-Bromo-indan-1-one 38b (6.02 g, 28.5 mmol) and iodoguanidine (4.4 mL, 70 mmol) were dissolved in 200 mL of THF (dry) and stirred at room temperature for 15 min. g, 68.2 mmol), stirring for 2 hours, TLC was monitored until the reaction of the starting material was completed, 150 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL×2), and the organic phase was washed with saturated brine. The mixture was dried over sodium sulfate, filtered and evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,, %.
'HNMR(400MHz, CDC13): δ 7.918(d, J=1.6Hz, 1H), 7.725(dd, J,=8Hz, J2=2Hz, 1H), 7.352(d, J=8Hz， 1H), 2.979(s, 2H), 1.273(s, 6H) 第二步 'HNMR (400MHz, CDC1 3 ): δ 7.918 (d, J = 1.6 Hz, 1H), 7.725 (dd, J, = 8 Hz, J 2 = 2 Hz, 1H), 7.352 (d, J = 8 Hz, 1H), 2.979(s, 2H), 1.273(s, 6H) Step 2
5-溴 -2,2-二甲基茚满 5-bromo-2,2-dimethylindole
将 6-溴 -2,2-二甲基茚满 -1-酮 45a(7.23 g, 30.3 mmol)溶解于 150 mL三氟醋酸中， 加入三乙基硅烷 (12.1 mL， 75.6 mmol), 室温搅拌过夜， TLC监测反应至原料反应 完全， 加水淬灭反应， 反应液减压浓缩除去三氟醋酸， 加入饱和碳酸钠调节 pPHi 至碱性， 用乙酸乙酯萃取 (50 mLx3)， 合并有机相， 有机相用饱和食盐水洗涤， 无
水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产物 5-溴 -2,2- 二甲基茚满 45b(14 g， 无色油状液体)， 直接投下一歩反应。 Dissolve 6-bromo-2,2-dimethylindan-1-one 45a (7.23 g, 30.3 mmol) in 150 mL of trifluoroacetic acid, add triethylsilane (12.1 mL, 75.6 mmol), stir at room temperature Overnight, TLC monitors the reaction until the reaction of the starting material is complete. The reaction mixture is quenched with water. The reaction mixture is concentrated under reduced pressure to remove trifluoroacetic acid. The mixture is adjusted to ppHi to basic with saturated sodium carbonate, extracted with ethyl acetate (50 mL×3), combined organic phase, organic Wash with saturated saline, no The aqueous solution was dried over sodium sulfate, and filtered, and then filtered, evaporated, evaporated, evaporated, evaporated, evaporated.
'HNMR(400MHz, CDC13): δ 7.335(s,lH), 7.281(d, J=8Hz, 1 H), 7.063(s, J=8Hz, 1H), 2.749(s, 2H), 2.702(s, 2H), 1.188(s, 6H) 第三步 'HNMR (400MHz, CDC1 3 ): δ 7.335(s,lH), 7.281(d, J=8Hz, 1 H), 7.063(s, J=8Hz, 1H), 2.749(s, 2H), 2.702(s , 2H), 1.188(s, 6H) Step 3
1 -(2,2-二甲基茚满 -5-基)肼 - 1 ,2-二甲酸二叔丁酯 将 5-溴 -2,2-二甲基茚满 45b(2.4 g， 10.7 mmol)溶解于 20 mL四氢呋喃 (干燥)中， 用干冰 /乙醇浴冷却至 -78°C， 滴加正丁基锂 (12.1 mL， 30.2 mmol), 加毕搅拌 2小 时， 将偶氮二甲酸二叔丁酯 (3.27 g， 14.2 mmol)溶解于 20 mL四氢呋喃 (干燥)， 加 入到上述反应液中， 继续低温反应 3小时， TLC监测至原料反应完全， 用 50 mL 水淬灭反应， 反应液用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 有机相用饱和食盐 水洗涤， 无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产 物 1-(2，2-二甲基茚满- 5-基)肼 -1,2-二甲酸二叔丁酯 45c(2.68 g， 黄色油状液体)， 产 率： 66.8%。 第四歩 1-(2,2-Dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-tert-butyl ester 5-bromo-2,2-dimethylindane 45b (2.4 g, 10.7 mmol Dissolve in 20 mL of tetrahydrofuran (dry), cool to -78 ° C with dry ice / ethanol bath, add n-butyl lithium (12.1 mL, 30.2 mmol) dropwise, add 2 hours of stirring, add azodicarboxylate Butyl ester (3.27 g, 14.2 mmol) was dissolved in 20 mL of tetrahydrofuran (dry), added to the above reaction solution, and the reaction was continued for 3 hours. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched with 50 mL of water. The ethyl ester was extracted (50 mL×2), and the organic phase was combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate Methyl indane-5-yl)pyridin-1,2-dicarboxylic acid di-tert-butyl ester 45c (2.68 g, yellow oily liquid), yield: 66.8%. Fourth
2-(2,2-二甲基茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 将 1-(2，2-二甲基茚满 -5-基)肼 -1,2-二甲酸二叔丁酯 45c(3.3 g， 8.78 mmol)溶解于 12 mL乙酸中， 加入 6 mL三氟乙酸和 3-氧代-丁酸甲酯 (1.5 mL， 13.8 mmol), 加毕 于 90°C下搅拌 2小时， TLC监测反应至原料反应完全， 反应液减压浓缩， 向残余 物中加入 30 mL水和 30 mL乙酸乙酯， 搅拌均匀后分液， 有机相用饱和食盐水洗 涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩后柱层析得到标题产物 2-(2,2- 二甲基茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 45d(464 mg， 黄色油状液体)， 产率： 22.1%。 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 1-(2,2-dimethylindan-5 -Phenyl-1,2-dicarboxylic acid di-tert-butyl ester 45c (3.3 g, 8.78 mmol) was dissolved in 12 mL of acetic acid, and 6 mL of trifluoroacetic acid and methyl 3-oxo-butyrate (1.5 mL, 13.8 mmol), stirred at 90 ° C for 2 hours, TLC was monitored until the reaction of the starting material was complete, and the reaction mixture was concentrated under reduced pressure. To the residue was added 30 mL of water and 30 mL of ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate Methyl-2,4-dihydropyrazol-3-one 45d (464 mg, yellow oily). Yield: 22.1%.
MS m/z (ESI): 243.3[M+1] 第五步 MS m/z (ESI): 243.3 [M+1] Step 5
5— (3— {Ν'— [卜 (2,2—二甲基茚满 -5—基 )-3—甲基— 5—氧代— ^5-二氢吡唑— 4—亚基]—肼基 }-2-轻 基苯:) -呋喃 -2-羧酸 5 — (3 — {Ν '— [Bu (2 , 2 - dimethylindan- 5 -yl) -3 -methyl-5-oxo-^5-dihydropyrazole- 4 -subunit] —肼基} - 2 -light benzene :) -furan-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸氢溴酸盐 9c (150 mg, 0.5 mmol)溶 解于盐酸 (1.7 mL, 1 mol/L)中， 滴加入 0.6 mL亚硝酸钠溶液 (38 mg, 0.55 mmol), 反 应 20分钟，再加入 2-(2,2-二甲基茚满 -5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 45d (109 mg, 0.45 mmol), 分批加入碳酸氢钠 (630 mg， 7.5 mmol)禾 tH mL乙醇， 室温反应过夜。 TLC跟踪至原料消失， 过滤， 固体加入 15 mL水， 用浓盐酸调节 pH值至 3〜4， 过滤，滤饼用乙酸乙酯洗涤 (1 mLx3)后干燥得到标题产物 5-(3-{Ν'-[1 -(2,2-二甲基茚 满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 }-2-羟基苯) -呋喃 -2-羧酸 45(67
mg, 黄色固体)， 产率： 31.6%。 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (150 mg, 0.5 mmol) was dissolved in hydrochloric acid (1.7 mL, 1 mol/L). Add 0.6 mL of sodium nitrite solution (38 mg, 0.55 mmol) dropwise for 20 minutes, then add 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-di Hydropyrazol-3-one 45d (109 mg, 0.45 mmol) was added portionwise sodium bicarbonate (630 mg, 7.5 mmol) and EtOAc. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1 mL×3) and dried to give the title product 5-(3-{Ν '-[1 -(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2-hydroxybenzene)-furan-2-carboxylic acid 45 (67 Mg, yellow solid), Yield: 31.6%.
MS m/z (ESI): 470.7[M-1] MS m/z (ESI): 470.7 [M-1]
lHNMR(400MHz,DMSO-i/6): 51.13(s,6H),2.32(s,3H),2.70(m,4H),7.14(d,J=3.6Hz,lH), 7.21 (m,2H),7.36(d,J=3.6Hz, 1 H),7.54(m, 1 H),7.62(m, 1 H),7.69(m,2H) 实施例 46 lHNMR (400MHz, DMSO-i/6): 51.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 (d, J = 3.6 Hz, lH), 7.21 (m, 2H) , 7.36 (d, J = 3.6 Hz, 1 H), 7.54 (m, 1 H), 7.62 (m, 1 H), 7.69 (m, 2H).
5-{2-羟基 -3-ΓΝ'-Π-茚满 -5-基 -3甲基 -5-氧代 -L5-二氢吡唑 -4-亚基) -肼基 1- 5-甲基苯 5-{2-hydroxy-3-ΓΝ'-Π-indan-5-yl-3methyl-5-oxo-L5-dihydropyrazole-4-ylidene)-indenyl 1- 5- Base benzene
第一步 First step
5-(3-硝基 -2-甲氧基 -5-甲基苯基) -呋喃 -2-羧酸 将 3-(4,5-二甲基 -[1,3,2]硼酸频那醇酯 -2-基) -2-甲氧基 -5-甲基-硝基苯 24a (3.1 g, 5-(3-nitro-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 3-(4,5-dimethyl-[1,3,2]boronic acid Alcohol ester-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (3.1 g,
7.5 mmol), 5-溴 -呋喃 -2-羧酸 (1.3 g， 6.8 mmol)、 四 (三苯基膦)钯 (0.43 g， 0.4 mmol) 和碳酸钠（1.6 g, 15.1 mmol)加入到 30 mLl,4-二氧六环和 15 mL水的混合溶剂中， 反应体系加热回流 1 小时， TLC跟踪至原料消失， 反应液冷却后过滤， 滤液用乙 酸乙酯洗涤后减压浓缩， 所得固体中加入 50 mL水， 用浓盐水调节 pH值至 3， 过 滤， 滤饼用乙酸乙酯洗涤后干燥得到标题产物 5-(3-硝基 -2-甲氧基 - 5-甲基苯基) -呋 喃 -2-羧酸 46a(522 mg， 黄色固体)， 产率： 29%。 7.5 mmol), 5-bromo-furan-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol) were added to 30 In a mixed solvent of mLl, 4-dioxane and 15 mL of water, the reaction system was heated under reflux for 1 hour, and the residue was evaporated to dryness. The reaction mixture was cooled and filtered, and the filtrate was washed with ethyl acetate. 50 mL of water was added, the pH was adjusted to 3 with brine, filtered, and the filtered cake was washed with ethyl acetate and dried to give the title product 5-(3-nitro-2-methoxy- 5-methylphenyl) Furan-2-carboxylic acid 46a (522 mg, yellow solid), Yield: 29%.
MS m/z (ESI): 275.7[M-1] MS m/z (ESI): 275.7 [M-1]
'HNMR(400MHz, DMSO- 6): δ 13.31(1H, br), 7.90(1 H, s)， 7.78(1H, s), 7.39(1 H, d， 'HNMR (400 MHz, DMSO-6): δ 13.31 (1H, br), 7.90 (1H, s), 7.78 (1H, s), 7.39 (1 H, d,
J=3.2Hz), 7.16(1 H, d， J=3.6Hz), J=3.2Hz), 7.16(1 H, d, J=3.6Hz),
3.80(3H,s) , 2.42(3H,s) 3.80(3H,s), 2.42(3H,s)
第二步 Second step
5-(3-氨基 -2-甲氧基 -5-甲基苯基) -呋喃 -2-羧酸
将 5-(3-硝基 -2-甲氧基 -5-甲基苯基;) -呋喃 -2-羧酸 46a(410 mg, 1.48 mmol)溶解于 28niL乙酸乙酯中， 加入 61 mg钯 -碳和甲酸铵 (658 mg, 10.44 mmol)， 加毕加热回 流 3小时。 TLC跟踪至原料消失， 过滤除去钯 -碳， 滤液减压浓缩， 干燥， 得到标 题产物 5-P-氨基 -2-甲氧基 -5-甲基苯基) -呋喃 -2-羧酸 46b(356 mg,白色固体)。产率： 97.3%。 5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid Dissolve 5-(3-nitro-2-methoxy-5-methylphenyl;)-furan-2-carboxylic acid 46a (410 mg, 1.48 mmol) in 28 mL of ethyl acetate and add 61 mg of palladium. - Carbon and ammonium formate (658 mg, 10.44 mmol), heated to reflux for 3 h. The TLC was traced to the disappearance of the starting material, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(p-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46b ( 356 mg, white solid). Yield: 97.3%.
MS m/z (ESI): 246.0[M-1] MS m/z (ESI): 246.0 [M-1]
'HNMR(400MHz, DMSO-C/(5): δ 7.18(l H,s) , 6.98(lH,m), 6.80(lH,s), 6.56(lH,s), 3.62(3H,s), 2.20(3H,s) 第三步 'HNMR (400 MHz, DMSO-C/(5): δ 7.18 (l H, s), 6.98 (lH, m), 6.80 (lH, s), 6.56 (lH, s), 3.62 (3H, s), 2.20(3H,s) Step 3
5-(3-氨基 -2-羟基 -5-甲基苯基) -呋喃 -2-羧酸氢溴酸盐 将 5-(3-氨基 -2-甲氧基 -5-甲基苯基) -呋喃 -2-羧酸 46b (248 mg, 1 mmol)溶解于 20 mL二氯甲垸中， 滴加入三溴化硼的二氯甲垸溶液 (3 mL, 1 mmol/L), 室温反应 2 小时。 TLC跟踪至原料消失， 减压浓缩， 所得固体用乙酸乙酯洗涤 (50 mLx3)， 干 燥后得到标题产物 5-(3-氨基 -2-羟基 -5-甲基苯基) -呋喃 -2-羧酸氢溴酸盐 46c(172 mg, 白色固体)。 产率： 54.7%。 5-(3-Amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 5-(3-amino-2-methoxy-5-methylphenyl) -furan-2-carboxylic acid 46b (248 mg, 1 mmol) was dissolved in 20 mL of dichloromethane, and a solution of boron tribromide in dichloromethane (3 mL, 1 mmol/L) was added dropwise. hour. TLC was traced to the disappearance of the material, which was evaporated to dryness. Carboxylic acid hydrobromide 46c (172 mg, white solid). Yield: 54.7%.
MS m/z (ESI): 231.8[M-1] MS m/z (ESI): 231.8 [M-1]
'HNMR(400MHz, DMSO- 6): δ 7.46(1 H,m) , 7.34(lH,m)， 7.10(2H,m) , 2.31(3H,s) 第四歩 'HNMR (400MHz, DMSO-6): δ 7.46 (1 H, m), 7.34 (lH, m), 7.10 (2H, m), 2.31 (3H, s)
5-{2-羟基 -3-[N'-(l -茚满 -5-基 -3甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 ]-5-甲基苯 呋喃 -2-羧酸 5-{2-hydroxy-3-[N'-(l-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl] -5-methylbenzylfuran-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基 -5-甲基苯基) -呋喃 -2-羧酸氢溴酸盐 46c (219 mg, 0.70 mmol) 溶解于 2.3 mL IN盐酸中， 滴加入 1.0 mL亚硝酸钠溶液 (53 mg, 0.77 mmol),反应 20分钟，再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (134 mg, 0.63 mmol),分批加入碳酸氢钠 (878 mg, 10.45 mmol)和 2 mL乙醇，室温反应过夜。 TLC 跟踪至原料消失， 过滤， 固体加入到 20mL水中， 冰浴下用浓盐酸调节 Ph=3〜4， 过滤，滤饼用 6 mL二氯甲烷洗涤后干燥，得到标题产物 5-{2-羟基 -3-[Ν'-(1-茚满 -5- 基 -3甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 ]-5-甲基苯 } -呋喃 -2-羧酸 46(170 mg, 红色固体)。 产率： 59.2%。 Dissolve 5-(3-amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (219 mg, 0.70 mmol) in 2.3 mL of IN hydrochloric acid under ice-cooling Add 1.0 mL of sodium nitrite solution (53 mg, 0.77 mmol) for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (134 Mg, 0.63 mmol), sodium hydrogencarbonate (878 mg, 10.45 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 20 mL of water. The mixture was adjusted to Ph = 3 to 4 with concentrated hydrochloric acid under ice-cooling, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{2-hydroxyl -3-[Ν'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-5-methylbenzene } -furan-2-carboxylic acid 46 (170 mg, red solid). Yield: 59.2%.
MS m/z (ESI): 456.8[M-1] MS m/z (ESI): 456.8 [M-1]
"HNMR(400MHz, DMSO-t/d): 5 2.05(m, 2H), 2.32(s, 3H), 2.37(s, 3H), 2.88(m, 4H), 7.13(d, J=3.6Hz, 1 H), 7.28(d, J=8.0Hz, 1 H), 7.35(m, 2H), 7.51(s, 1 H), 7.68(d, J=7.6Hz, 1H), 7.78(s, 1H) 实施例 47 "HNMR (400MHz, DMSO-t/d): 5 2.05 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 2.88 (m, 4H), 7.13 (d, J = 3.6 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.35 (m, 2H), 7.51 (s, 1 H), 7.68 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H) Example 47
2-ί2-经基 -3-ΓΝ'-(1-茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 1-苯}-5-甲
基 -噻唑 -4-羧酸 2-ί2-carbyl-3-ΓΝ'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1 -Benzene-5-A Thiazole-carboxylic acid
2-(2-甲氧基 -3-硝基苯基) -5-甲基 -噻唑 -4-羧酸 将 2-(2-甲氧基 -3-硝基苯基) -4,4，5,5-四甲基 -[1,3,2]硼酸乙二醇酯 6a(1.7 g, 6.08 mmol)、 2-溴 -5-甲基 -噻唑 -4-羧酸 (900 mg, 4.05 mmol)、 四 (三苯基膦)钯 (233 mg, 0.2 mmol)和碳酸钠（1.29 g, 12.16 mmol)溶解于 30mL 1,4-二氧六环中，加热回流 4小时。 TLC跟踪至原料消失， 过滤， 滤液减压浓缩， 向残余物中加入 20 mL盐酸 (IN)和 30 mL乙酸乙酯， 搅拌后静置分液， 将有机相用饱和氯化钠溶液洗涤， 无水硫酸钠 干燥， 过滤除去干燥剂， 滤液减压浓缩后用乙酸乙酯和正己烷的混合溶剂重结晶， 所得固体干燥后得到标题产物 2-(2-甲氧基 -3-硝基苯基) -5-甲基 -噻唑 -4-羧酸 47a (310 mg, 黄色固体)。 产率： 26%。 2-(2-methoxy-3-nitrophenyl)-5-methyl-thiazole-4-carboxylic acid 2-(2-methoxy-3-nitrophenyl)-4,4, 5,5-Tetramethyl-[1,3,2]borate 6a (1.7 g, 6.08 mmol), 2-bromo-5-methyl-thiazole-4-carboxylic acid (900 mg, 4.05 mmol Tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (1.29 g, 12.16 mmol) were dissolved in 30 mL of 1,4-dioxane and heated to reflux for 4 hours. The TLC was traced to disappearance of the starting material, and the filtrate was concentrated under reduced pressure. To the residue was added 20 mL of hydrochloric acid (IN) and 30 mL of ethyl acetate. After stirring, the mixture was separated and the organic phase was washed with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, and the residue was evaporated to dryness. -5-Methyl-thiazole-4-carboxylic acid 47a (310 mg, yellow solid). Yield: 26%.
MS m/z (ESI): 292.6[M-1] MS m/z (ESI): 292.6 [M-1]
'HNMR(400MHz, DMSO- 6): δ 13.45(br, 1H), 8.58(dd, J=8.0, 1H)， 8.14(dd, J=8.0, 1H), 7.52(t, J=8.0, 1H), 3.93(s, 3H), 2.71(s, 3H) 第二步 'HNMR (400MHz, DMSO- 6 ): δ 13.45 (br, 1H), 8.58 (dd, J = 8.0, 1H), 8.14 (dd, J = 8.0, 1H), 7.52 (t, J = 8.0, 1H) , 3.93(s, 3H), 2.71(s, 3H) Step 2
2-(2-甲氧基 -3-氨基-苯基) -5-甲基-噻唑 -4-羧酸 将 2-(2-甲氧基 -3-硝基苯基) -5-甲基 -噻唑 -4-羧酸 47a (300 mg, 1.02 mmol)溶解 于 15 mL甲醇中， 加入 30 mg钯 -碳， 于氢气氛下搅拌 24小时。 TLC跟踪至原料 消失， 反应液过滤除去钯 -碳， 滤液减压浓缩得到标题产物 2-(2-甲氧基 -3-氨基-苯 基) -5-甲基 -噻唑 -4-羧酸 47b(250 mg， 黄色固体)， 产率： 92%。 2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 2-(2-methoxy-3-nitrophenyl)-5-methyl - Thiazole-4-carboxylic acid 47a (300 mg, 1.02 mmol) was dissolved in 15 mL of methanol, 30 mg of palladium-carbon was added, and stirred under a hydrogen atmosphere for 24 hours. TLC was traced to disappearance of the starting material, and the reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to give the title product 2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 47b. (250 mg, yellow solid), Yield: 92%.
MS m/z (ESI): 262.8ΓΜ-1]
卜 MS m/z (ESI): 262.8ΓΜ-1] Bu
2-(2-羟基 -3-氨基-苯基) -5-甲基 -噻唑 -4-羧酸氢溴酸盐 将 2-(2-甲氧基 -3-氨基-苯基) -5-甲基 -噻唑 -4-羧酸 47b (280 mg, 0.94 mmol)溶解 于 5 mL溴化氢中， 于 80°C下搅拌过夜。 TLC跟踪至原料消失， 反应液过滤， 滤 饼用乙酸乙酯洗涤后干燥， 得到标题产物 2-(2-羟基 -3-氨基-苯基) -5-甲基 -噻唑 -4- 羧酸氢溴酸盐 47c (200 mg， 黄色固体)。 产率： 64%。 2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide 2-(2-methoxy-3-amino-phenyl)-5- Methyl-thiazole-4-carboxylic acid 47b (280 mg, 0.94 mmol) was dissolved in 5 mL of hydrogen bromide and stirred at 80 ° C overnight. The TLC was traced until the starting material disappeared, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrogen. Bromate 47c (200 mg, yellow solid). Yield: 64%.
MS m/z (ESI): 262.7[M-1] MS m/z (ESI): 262.7 [M-1]
'HNMR(400MHz, DMSO-i¾): 67.88(d, J=8.0,1 H), 7.5 l(d, J=8.0， 1H), 7.09(t, J=8.0, lH), 2.73(s, 3H) 第四步 'HNMR (400MHz, DMSO-i3⁄4): 67.88 (d, J = 8.0, 1 H), 7.5 l (d, J = 8.0, 1H), 7.09 (t, J = 8.0, lH), 2.73 (s, 3H) ) the fourth step
2-{2-羟基 -3-[N'-(l -茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基)-肼基] -苯 }-5-甲 基 -噻唑 -4-羧酸 2-{2-hydroxy-3-[N'-(l-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-Benzene-5-methyl-thiazole-4-carboxylic acid
冰浴下将 2-(2-羟基 -3-氨基-苯基) -5-甲基 -噻唑 -4-羧酸氢溴酸盐 47c (200 mg, 0.60 mmol)溶解于 2 mL盐酸 (IN)中， 滴加入 0.82 mL亚硝酸钠溶液 (46 mg, 0.66 mmol), 搅拌 20分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (116 mg, 0.544 mmol),分批加入饱和碳酸氢钠溶液 (781 mg, 9.3 mmol)将 pH调至 8〜9，用 2 mL乙醇淬灭气泡， 升至室温反应过夜。 TLC跟踪至原料消失， 过滤出固体， 固体 用 20 mL水溶解， 浓盐酸调 pH = 3〜4， 过滤， 干燥， 粗品用 HPLC分离纯化， 得 到标题产物 2-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基) -肼 基] -苯 5-甲基 -噻唑 -4-羧酸 47 (195 mg， 红色固体)。 产率： 75.9%。 2-(2-Hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide 47c (200 mg, 0.60 mmol) was dissolved in 2 mL hydrochloric acid (IN). Add 0.82 mL of sodium nitrite solution (46 mg, 0.66 mmol) dropwise, stir for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one Li (116 mg, 0.544 mmol) was added portionwise with saturated sodium bicarbonate solution (781 mg, 9.3 mmol). The mixture was adjusted to pH 8 to 9 and quenched with 2 mL of ethanol. The TLC was traced to the disappearance of the starting material, the solid was filtered, the solid was dissolved in 20 mL of water, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 2-{2-hydroxy-3-[ '-(1-Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-benzene 5-methyl-thiazole-4 - Carboxylic acid 47 (195 mg, red solid). Yield: 75.9%.
MS m/z (ESI): 473.7[M-1] MS m/z (ESI): 473.7 [M-1]
1丽 MR(400MHz, D20): δ 1.97(m, 2H), 2.3 l (s, 3H), 2.53(s, 3H), 2.80(m, 4H), 6.52(t, J=8.0Hz, 1H), 7.23(m, 4H), 7.84(d, J=8.0Hz, 1H) 实施例 48 1 MN MR (400 MHz, D 2 0): δ 1.97 (m, 2H), 2.3 l (s, 3H), 2.53 (s, 3H), 2.80 (m, 4H), 6.52 (t, J = 8.0 Hz, 1H), 7.23 (m, 4H), 7.84 (d, J = 8.0 Hz, 1H) Example 48
{2-羟基 -3-ί '-(1-茚满 -5-基- 3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 1-苯 }-l，2，4- 三甲基 -1H-吡咯 -3-羧酸乙酯
{2-hydroxy-3-ί '-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1-benzene }-l,2,4-Trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester
冰浴下， 将 5-(3-氨基 -2-羟基苯基) -1,2,4-三甲基 -1H-吡咯 -3-羧酸乙酯氢溴酸盐 6h (180 mg, 0.66 mmol)溶解于 2.2 mL盐酸 (IN)中，滴加入 0.8 mL亚硝酸钠溶液 (50 mg, 0.72 mmol)，搅拌 20分钟，再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (126 mg, 0.59 mmol), 用饱和碳酸氢钠溶液 pH调至 8〜9， 用 2 mL乙醇淬灭气泡， 升 至室温反应过夜。 TLC跟踪至原料消失， 过滤出固体， 加入 20 mL二氯甲垸和 20 mL水， 搅拌均匀后用浓盐酸调剂 pH = 3〜4， 分液， 有机相用饱和食盐水洗涤， 无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后柱层析得到标题产物 5-{2-羟 基 3-[Ν'— (1—茚满—5—基—3—甲基—5—氧代— 1 二氢吡唑—4-亚基) -肼基] -苯 }-1,2，4-三甲基 -1Η-吡咯 -3-羧酸乙酯 48 (80 mg， 红色固体)。 产率： 25.8%。 5-(3-Amino-2-hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6 h (180 mg, 0.66 mmol) Dissolved in 2.2 mL of hydrochloric acid (IN), added 0.8 mL of sodium nitrite solution (50 mg, 0.72 mmol), stirred for 20 minutes, and then added 2-indan-5-yl-5-methyl-2,4 - Dihydropyrazol-3-one li (126 mg, 0.59 mmol), adjusted to pH 8~9 with saturated sodium bicarbonate solution, quenched with 2 mL of ethanol and warmed to room temperature overnight. After TLC traced to the disappearance of the starting material, the solid was filtered out, and 20 mL of dichloromethane and 20 mL of water were added. After stirring, the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, and the organic phase was washed with saturated brine. Drying, filtering and removing the desiccant, and concentrating the filtrate under reduced pressure, and then column chromatography to obtain the title product 5-{2-hydroxy 3 -[Ν'- (1 - indane-5-yl-3-methyl-5-oxo- 1 dihydropyrazole-4-nyl)-indenyl]-phenyl}-1,2,4-trimethyl-1Η-pyrrole-3-carboxylic acid ethyl ester 48 (80 mg, red solid). Yield: 25.8%.
MS m/z (ESI): 514.0[M+1] MS m/z (ESI) : 514.0 [M+1]
'HNMR(400MHz, DMSO-i/6): 51.30(m,3H), 2.01(m,2H), 2.23(s,3H), 2.50(s,3H), 2.95(m,4H), 3.32(s,3H)， 4.33(m,2H), 6.63(m,lH), 7.00(m,lH), 7.12(m,lH), 7.28(m,lH): 7.73(m,2H), 13.91(br,lH) 实施例 49 'HNMR (400MHz, DMSO-i/ 6 ): 51.30 (m, 3H), 2.01 (m, 2H), 2.23 (s, 3H), 2.50 (s, 3H), 2.95 (m, 4H), 3.32 (s) , 3H), 4.33 (m, 2H), 6.63 (m, lH), 7.00 (m, lH), 7.12 (m, lH), 7.28 (m, lH) : 7.73 (m, 2H), 13.91 (br, lH) Example 49
5-(2-羟基 -3-{Ν'-「3-甲基 -5-氧代 -1-(1,U,3-四甲基茚满 -5-基) -1,5-二氢吡唑 -4-亚基卜 肼基 } -苯) -噻吩 -2-羧酸 5-(2-hydroxy-3-{Ν'-"3-methyl-5-oxo-1-(1,U,3-tetramethylindan-5-yl)-1,5-dihydro Pyrazole-4-indolyl}-phenyl)-thiophene-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 12c (260 mg, 0.823 mmol) 溶解于 2.7 mL盐酸 (IN)中， 滴加入 1.1 mL亚硝酸钠溶液 (62 mg, 0.91 mmol), 搅拌 20分钟，再加入 5-甲基 -2-(1,1,3,3-四甲基茚满 -5基) -2,4-二氢吡唑 -3-酮 19d (200 mg, 0.74 mmol), 用饱和碳酸氢钠溶液调节 pH值至 8， 用 2 mL乙醇淬灭气泡， 升至室 温反应 3小时。 TLC跟踪至原料消失， 过滤出固体， 固体中加入 20 mL水， 用浓 盐酸调 pH = 3〜4, 过滤， 固体干燥后经柱层析得到标题产物 5-(2-羟基 -3-{N'-[3-
甲基 -5-氧代 1,3,3-四甲基茚满 -5-基) -1，5-二氢吡唑 -4-亚基] -肼基 苯) -噻吩 -2- 羧酸 49 (216 mg， 红色固体)。 产率： 56.5%。 5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (260 mg, 0.823 mmol) was dissolved in 2.7 mL of hydrochloric acid (IN) under ice bath, and 1.1 mL was added dropwise. Sodium nitrite solution (62 mg, 0.91 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydrogen Pyrazol-3-one 19d (200 mg, 0.74 mmol) was adjusted to pH 8 using a saturated aqueous sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature for 3 hours. The TLC was traced to disappearance of the starting material, and the solid was filtered. 20 mL of water was added to the solid. The mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried to give the title product 5-(2-hydroxy-3-{N '-[3- Methyl-5-oxo 1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene]-mercaptophenyl)-thiophene-2-carboxylic acid 49 (216 mg, red solid). Yield: 56.5%.
'HNMR(400MHz, DMSO-i 6): δ 1.30(m, 12H), 1.93(s, 2H), 2.34(s, 3H), 7.19(t, J=8.0Hz, 1H), 7.25(d, J=8.0Hz， 1H), 7.57(d, J=8.0Hz, 1H), 7.66(m, 2H), 7.7 l(d, J=8.0Hz, 1H), 7.77(m, 2H), 10.10(s, 1H), 13.06(br, 1H), 13.72(br, 1H) 实施例 50 'HNMR (400MHz, DMSO-i 6): δ 1.30 (m, 12H), 1.93 (s, 2H), 2.34 (s, 3H), 7.19 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.66 (m, 2H), 7.7 l (d, J = 8.0 Hz, 1H), 7.77 (m, 2H), 10.10 (s, 1H), 13.06(br, 1H), 13.72(br, 1H) Example 50
5- 2-羟基 -5-甲基 -3-{Ν'-Γ3-甲基 -5-氧代 -1 - (5,6,7,8-四氢萘 -2-基) -1.5-二氢吡唑 -4-亚 基卜肼基 苯) -呋喃 -2-羧酸 5- 2-Hydroxy-5-methyl-3-{Ν'-Γ3-methyl-5-oxo-1 - (5,6,7,8-tetrahydronaphthalen-2-yl)-1.5- Hydropyrazol-4-ylidenebenylbenzene)-furan-2-carboxylic acid
冰浴下将 5-(3-氨基 -2-羟基 -5-甲基苯基) -呋喃 -2-羧酸氢溴酸盐 46c (120 mg, 0.38 mmol) 溶解于 1.3 mL IN盐酸中， 滴加入 0.5 mL亚硝酸钠溶液 (29 mg, 0.42 mmol), 反应 20分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (78 mg, 0.34 mmol), 用饱和碳酸氢钠溶液调节 pH至 8， 加入 2 mL乙醇， 室温反 应过夜。 TLC跟踪至原料消失， 过滤， 固体加入到 20 mL水中， 再用浓盐酸调节 pH=3〜4， 过滤， 固体干燥后经柱层析得到标题产物 5-(2-羟基 -5-甲基 -3-{N'-[3-甲 基 -5-氧代 -1-(5,6,7,8-四氢萘 -2-基) -1 ,5-二氢吡唑 -4-亚基] -肼基 苯) -呋喃 -2-羧酸 50 (56 mg, 红色固体)。 产率： 34.8%。 Dissolve 5-(3-amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (120 mg, 0.38 mmol) in 1.3 mL of IN hydrochloric acid under ice-cooling. Add 0.5 mL of sodium nitrite solution (29 mg, 0.42 mmol) for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4- Dihydropyrazol-3-one 3i (78 mg, 0.34 mmol) was adjusted to pH 8 using a saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-5-methyl- 3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene ] - mercaptobenzene) - furan-2-carboxylic acid 50 (56 mg, red solid). Yield: 34.8%.
MS m/z (ESI): 470.8[M-1] MS m/z (ESI): 470.8 [M-1]
'HNMR(400MHz, DMSO-C 6): δ 1.75(m, 4H), 2.3 l (s, 3H), 2.37(s, 3H), 2.73(m, 4H), 7.13(m, 2H), 7.35(m, 2H), 7.50(s, 1H), 7.62(m, 2H) 实施例 51 'HNMR (400MHz, DMSO-C 6): δ 1.75 (m, 4H), 2.3 l (s, 3H), 2.37 (s, 3H), 2.73 (m, 4H), 7.13 (m, 2H), 7.35 ( m, 2H), 7.50 (s, 1H), 7.62 (m, 2H) Example 51
4-(2-羟基 -3-W'-「3-甲基 -5-氧代 -l-(5,6.7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基 1-肼 基 苯) -噻吩 -2-羧酸 4-(2-hydroxy-3-W'-"3-methyl-5-oxo-l-(5,6.7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole- 4-substyl 1-mercaptophenyl)-thiophene-2-carboxylic acid
第一歩 First
4-(3-硝基 -2-甲氧基-苯基) -噻吩 -2-羧酸 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid
将 2-(2-甲氧基 -3-硝基苯基)- 4,4,5,5-四甲基 -[1 ,3,2]硼酸乙二醇酯 6a (0.81 g, 2.9 mmol), 4-溴 -噻吩 -2-羧酸 (0.3 g, 1.45 mmol), 四 (三苯基膦)钯 (80 mg, 0.073 mmol) 和碳酸钠 (0.31 g， 2.9 mmol)溶解于 20 mL 1,4-二氧六环和 10 mL水的混合溶剂中， 加热回流 0.5小时。 TLC跟踪至原料消失， 反应液用 1N盐酸酸化至 pH〜3， 乙酸 乙酯萃取 (20 mLx3) , 合并有机相， 有机相减压浓缩后柱层析得到标题产物 4-(3- 硝基 -2-甲氧基-苯基) -噻吩 -2-羧酸 51a(0.54 g， 棕色油状液体)， 直接进行下步反应。 MS m/z (ESI): 277.6[M-1] 第二步 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1 ,3,2]borate 6a (0.81 g, 2.9 mmol) , 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) dissolved in 20 mL In a mixed solvent of 4-dioxane and 10 mL of water, the mixture was heated under reflux for 0.5 hour. After the TLC was traced to the disappearance of the starting material, the reaction mixture was acidified to pH~3 with 1N hydrochloric acid, ethyl acetate (20 mL×3), and the organic phase was combined, and the organic phase was concentrated under reduced pressure to give the title product 4-(3-nitro- 2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (0.54 g, brown oily liquid) was directly subjected to the next step. MS m/z (ESI): 277.6 [M-1] Step 2
4-(3-氨基 -2-甲氧基-苯基) -噻吩 -2-羧酸 4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid
将 4-(3-硝基 -2-甲氧基-苯基) -噻吩 -2-羧酸 51a (400 mg, 1.45 mmol)溶解于 30mL 乙酸乙酯中， 再加入 100 mg钯 -碳和甲酸胺 (360 mg, 5.8 mmol), 加热回流 3小时。 TLC跟踪至原料消失， 反应液过滤除去钯 /碳，减压浓缩得到标题产物 4- 3-氨基 -2- 甲氧基-苯基) -噻吩 -2-羧酸 51b(410 mg， 棕色油状液体） ， 直接进行下步反应。 MS m/z (ESI): 247.8[M-1] 第三步 Dissolve 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (400 mg, 1.45 mmol) in 30 mL of ethyl acetate, then add 100 mg of palladium-carbon and formic acid The amine (360 mg, 5.8 mmol) was heated to reflux for 3 h. The TLC was traced to disappearance of the starting material, and the reaction mixture was filtered to remove palladium/carbon, and concentrated under reduced pressure to give the title product 4- 3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (410 mg, brown oily liquid ), directly carry out the next step of the reaction. MS m/z (ESI): 247.8 [M-1] Step 3
4-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 将 4- 3-氨基 -2-甲氧基-苯基) -噻吩 -2-羧酸 51b (360 mg, 1.45 mmol)溶解于 5 mL 二氯甲烷中， 滴加入三溴化硼 (2.8 mL， 5.6 mmol)， 室温反应 4.5小时。 TLC跟踪至 原料消失， 加入 5 mL甲醇， 减压浓缩， 向残余物中加入 10 mL乙酸乙酯， 搅拌 0.5 小时， 过滤， 收集固体， 干燥， 得到标题产物 4-(3-氨基 -2-羟基苯基) -噻吩 -2- 羧酸氢溴酸盐 51c(80 mg， 灰色固体)。 产率： 17.5%。 4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt 4- 3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (360 Mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane, boron tribromide (2.8 mL, 5.6 mmol) was added dropwise, and the mixture was reacted at room temperature for 4.5 hours. TLC was traced to the disappearance of the starting material, and 5 mL of methanol was added, and the mixture was concentrated under reduced pressure. The residue was evaporated and evaporated. Phenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, grey solid). Yield: 17.5%.
MS m/z (ESI): 236.1 [M+l] 第四步 MS m/z (ESI): 236.1 [M+l] Step 4
4-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1-(5,6,7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基] -肼 基} -苯) -噻吩 -2-羧酸 . 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazol-4-ylidene]-fluorenyl}-phenyl)-thiophene-2-carboxylic acid.
冰浴下将 4-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 51c (80 mg, 0.25 mmol) 溶解于 1 mL IN盐酸中， 滴加入 0.3 mL亚硝酸钠溶液 (19 mg, 0.28 mmol), 反应 20 分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (52 mg, 0.23
mmol), 用饱和碳酸氢钠溶液调节 pH至 8， 加入 2 mL乙醇， 室温反应过夜。 TLC 跟踪至原料消失， 过滤， 固体加入到 20 mL水中， 再用浓盐酸调节 pH=3〜4， 过 滤， 固体中加入 4 mL乙酸乙酯搅拌 2小时， 过滤， 所得固体干燥后得到标题产物 4-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1- (5,6,7,8-四氢萘 -2-基) -1,5-二氢吡唑 -4-亚基] -肼 基 苯) -噻吩 -2-羧酸 51 (11 mg， 黑色固体)。 产率： 10.2%。 Dissolve 4-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, 0.25 mmol) in 1 mL of IN hydrochloric acid and add 0.3 mL of nitrous acid dropwise. Sodium solution (19 mg, 0.28 mmol), reacted for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-ketone 3i (52 mg, 0.23 Methyl), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 4 mL of ethyl acetate was added to the solid and stirred for 2 hours, filtered, and the obtained solid was dried to give the title product 4 -(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyridyl Imidazole-4-ylidene]-mercaptophenyl)-thiophene-2-carboxylic acid 51 (11 mg, black solid). Yield: 10.2%.
MS m/z (ESI): 472.8[M-1 ] MS m/z (ESI): 472.8 [M-1]
'HNMR(400MHz, DMSO-i 6): δ 1.76(m, 4H), 2.33(s， 3H), 2.74(m, 4H), 7.13(m, 2H), 7.33(m, 1H), 7.65(m, 3H), 8.06(d, J=1.6Hz, 1H), 8.14(d, J=1.6Hz, 1H), 9.68(s, 1H), 13.75(s, 1H) 实施例 52 'HNMR (400MHz, DMSO-i 6): δ 1.76 (m, 4H), 2.33 (s, 3H), 2.74 (m, 4H), 7.13 (m, 2H), 7.33 (m, 1H), 7.65 (m) , 3H), 8.06 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 9.68 (s, 1H), 13.75 (s, 1H) Example 52
4-{2-羟基 -3-ΓΝ'-Π-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基 1-苯 噻吩 4-{2-hydroxy-3-indole-indole-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- Phenylthiophene
-2-羧酸 2-carboxylic acid
冰浴下将 4-(3-氨基 -2-羟基苯基) -噻吩 -2-羧酸氢溴酸盐 51c(120 mg, 0.38 mmol) 溶解于 2.7 mL IN盐酸中， 滴加入 0.45 mL亚硝酸钠溶液 (29 mg, 0.42 mmol), 反应 20分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (73 mg, 0.34 mmol), 用 饱和碳酸氢钠溶液调节 pH至 8， 加入 2 mL乙醇， 室温反应过夜。 TLC跟踪至原 料消失， 过滤， 固体加入到 20 mL水中， 再用浓盐酸调节 pH=3〜4， 过滤， 固体 中加入 5 mL乙酸乙酯搅拌 1小时， 过滤， 所得固体干燥后得到标题产物 4-{2-羟 基 _3-[Ν'-(1-茚满 _5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -肼基]-苯} -噻吩 -2-羧酸 52(45 mg, 黄色固体)。 产率： 28.7%。 Dissolve 4-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (120 mg, 0.38 mmol) in 2.7 mL of IN hydrochloric acid and add 0.45 mL of nitrous acid dropwise. Sodium solution (29 mg, 0.42 mmol), react for 20 min, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (73 mg, 0.34 mmol) The pH was adjusted to 8 with a saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The TLC was traced to the disappearance of the starting material, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 5 mL of ethyl acetate was added to the solid and stirred for 1 hour, and filtered, and the obtained solid was dried to give the title product 4 -{2-hydroxy- 3- [Ν'-(1-indan_5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl] -Benzene-thiophene-2-carboxylic acid 52 (45 mg, yellow solid). Yield: 28.7%.
MS m/z (ESI): 458.8[M-1] MS m/z (ESI): 458.8 [M-1]
'HNMR(400MHz, DMSO- d): δ 2.05(m, 2H), 2.32(s, 3H), 2.87(m, 4H), 7.13(t,'HNMR (400MHz, DMSO-d): δ 2.05(m, 2H), 2.32(s, 3H), 2.87(m, 4H), 7.13(t,
J=8.0Hz, 1H), 7.32(m, 2H), 7.67(m, 2H), 7.78(s, 1H), 8.05(d, J=1.6Hz, 1H), 8.13(d, J=1.2Hz, 1H), 9.68(s, 1H), 13.79(s, 1H) 实施例 53 J=8.0Hz, 1H), 7.32(m, 2H), 7.67(m, 2H), 7.78(s, 1H), 8.05(d, J=1.6Hz, 1H), 8.13(d, J=1.2Hz, 1H), 9.68(s, 1H), 13.79(s, 1H) Example 53
-Q-羟基 -3-W'-「3-甲基 -5-氧代 -l-(5,6，7,8-四氢萘 -2-基) -1,5-二氢吡唑 1-4-亚基卜肼
第一步 -Q-hydroxy-3-W'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole 1 -4-Yakib first step
5-溴 -2-甲基呋喃 -3-羧酸甲酯 Methyl 5-bromo-2-methylfuran-3-carboxylate
将 2-甲基呋喃 -3-羧酸甲酯 (2.0 g， 14.3 mmol)溶解于苯中，加入偶氮二异丁腈 (10 mg, 0.06 mmol), 冰浴冷却至 0°C， 加入 N-溴代琥珀酰亚胺 (2.8 g， 15.7 mmol), 加毕撤去冰浴， 反应液于室温下搅拌过夜， TLC 跟踪至原料消失， 反应液过滤， 滤液减压浓缩后柱层析得到标题产物 5-溴 -2-甲基呋喃 -3-羧酸甲酯 53a(1.9 g， 无色 油状液体)， 产率： 61%。 第二步 Methyl 2-methylfuran-3-carboxylate (2.0 g, 14.3 mmol) was dissolved in benzene, azobisisobutyronitrile (10 mg, 0.06 mmol) was added, and cooled to 0 ° C in ice bath. - Bromosuccinimide (2.8 g, 15.7 mmol), the reaction mixture was stirred at room temperature overnight, and the mixture was stirred at room temperature overnight. Methyl 5-bromo-2-methylfuran-3-carboxylate 53a (1.9 g, colorless oily), yield: 61%. Second step
5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸甲酯 将 5-溴 -2-甲基呋喃 -3-羧酸甲酯 53a(0.65 g， 3.0 mmol)和 2-(2-甲氧基 -3-硝基苯 基) -4,4,5,5-四甲基 -[1,3,2]硼酸乙二醇酯 6a(1.0 g， 3.58 mmol)溶解于 1,4-二氧六环 (15 mL)中， 加入四 (三苯基膦)钯 (173 mg, 0.15 mmol)和碳酸钠 (636 mg, 6.0 mmol), 加 毕于 100Ό下回流 3小时， TLC跟踪至原料消失， 反应液冷却后过滤， 滤液减压浓 缩后经柱层析得到标题产物 5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸甲酯 53b(659 mg, 白色固体）。 产率： 75%。 第三步 Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate methyl 5-bromo-2-methylfuran-3-carboxylate 53a (0.65 g , 3.0 mmol) and 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (1.0 g , 3.58 mmol) dissolved in 1,4-dioxane (15 mL), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and sodium carbonate (636 mg, 6.0 mmol) After refluxing for 3 hours at 100 °C, TLC was traced until the starting material disappeared, and the reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to give the title product 5-(2-methoxy-3-nitrophenyl)-2- Methyl furan-3-carboxylate 53b (659 mg, white solid). Yield: 75%. third step
5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸 将 5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸甲酯 53b(650 mg, 2.23 mmol) 溶解于甲醇中，加入氢氧化钠 (268 mg, 6.7 mmol),加毕于 50°C下搅拌 3小时， TLC 跟踪至原料消失， 反应液减压浓缩后用 1N的盐酸调节 pH至 3〜4， 有大量固体析
出， 过滤， 所得固体用正己烷和乙酸乙酯的混合溶剂 (V:V=5:1)重结晶， 得到标题 产物 5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸 53c(450 mg， 白色固体 )， 产率： 84%。 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid 5-(2-methoxy-3-nitrophenyl)-2-methylfuran Methyl 3-carboxylate 53b (650 mg, 2.23 mmol) was dissolved in methanol, sodium hydroxide (268 mg, 6.7 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours, and the TLC was traced until the starting material disappeared. The liquid was concentrated under reduced pressure, and the pH was adjusted to 3 to 4 with 1N hydrochloric acid. The solid was recrystallized from a mixed solvent of n-hexane and ethyl acetate (V:V=5:1) to give the titled product 5-(2-methoxy-3-nitrophenyl)-2- Methylfuran-3-carboxylic acid 53c (450 mg, white solid), yield: 84%.
MS m/z (ESI): 275.7[M-1] MS m/z (ESI): 275.7 [M-1]
!HNMR(400MHz, DMSO- i¾):S12.80(s, 1H), 8.03(dd, J=8.0, 1H), 7.87(dd, J=8.0, 1H), 7.44(t, J=8.0, 1 H), 7.13(s, 1H), 3.83(s, 3H), 2.64(s, 3H) 第四歩 !HNMR (400MHz, DMSO-i3⁄4): S12.80(s, 1H), 8.03 (dd, J=8.0, 1H), 7.87 (dd, J=8.0, 1H), 7.44 (t, J=8.0, 1 H), 7.13(s, 1H), 3.83(s, 3H), 2.64(s, 3H)
5-(2-甲氧基 -3-氨基-苯基) -2-甲基呋喃 -3-羧酸 将 5-(2-甲氧基 -3-硝基苯基) -2-甲基呋喃 -3-羧酸 53c(450 mg, 1.62 mmol)溶解于 甲醇中， 加入 45 mg钯 /碳， 在氢气氛下回流搅拌 4小时， TLC跟踪至原料消失， 反应液过滤， 滤液减压浓缩得到标题产物 5-(2-甲氧基 -3-氨基-苯基) -2-甲基呋喃 -3- 羧酸 53d(370 mg， 白色固体)， 产率： 92%。 5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 5-(2-methoxy-3-nitrophenyl)-2-methylfuran 3-carboxylic acid 53c (450 mg, 1.62 mmol) was dissolved in methanol, 45 mg of palladium/carbon was added, and the mixture was stirred under reflux for 4 hours under a hydrogen atmosphere, and the residue was evaporated to the residue, and the filtrate was filtered. The product 5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 53d (370 mg, white solid).
MS m/z (ESI): 245.8[M-1] MS m/z (ESI): 245.8 [M-1]
'H MR(400MHz, CDC13): 66.97(s, 1H), 6.87(m, 2H), 6.68(m, 1H), 5.06(br, 2H),'H MR(400MHz, CDC1 3 ): 66.97(s, 1H), 6.87(m, 2H), 6.68(m, 1H), 5.06(br, 2H),
3.63(s, 3H)， 2.59(s, 3H) 第五步 3.63(s, 3H), 2.59(s, 3H) Step 5
5-(2-羟基 -3-氨基-苯基) -2-甲基呋喃 -3-羧酸氢溴酸盐 将 5-(2-甲氧基 -3-氨基-苯基； )-2-甲基呋喃 -3-羧酸 53dC370 mg， 1.5 mmol)溶解于 二氯甲垸中， 冰浴冷却至 0°C， 滴加三溴化硼的二氯甲垸溶液 (1 N， 3.6 mL) , 加毕 室温反应 2小时， TLC跟踪至原料消失， 反应液中加入 0.5 mL甲醇淬灭反应， 反 应液搅拌 30分钟后浓缩， 所得固体中加入 10 mL乙酸乙酯搅拌 30分钟， 过滤， 所得固体干燥后得到标题产物 5-(2-羟基 -3-氨基-苯基) -2-甲基呋喃 -3-羧酸氢溴酸盐 53e(240 mg , 灰色固体）， 产率： 46%。 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide salt 5-(2-methoxy-3-amino-phenyl; Methylfuran-3-carboxylic acid 53dC370 mg, 1.5 mmol) was dissolved in dichloromethane, cooled to 0 ° C in an ice bath, and a solution of boron tribromide in dichloromethane (1 N, 3.6 mL) was added dropwise. After the reaction was carried out for 2 hours at room temperature, TLC was followed until the disappearance of the starting material. The reaction mixture was quenched by the addition of 0.5 mL of methanol. The reaction mixture was stirred for 30 minutes and then concentrated. The obtained solid was added 10 mL ethyl acetate and stirred for 30 min. The title product 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide 53e (240 mg, m.
MS m/z (ESI): 231.7[M-1] MS m/z (ESI): 231.7 [M-1]
'HNMR(400MHz, CDC13): 57.57(dd, J=8.0, 1H), 7.24(dd, J=8.0, 1H), 7.05(t, J=8.0, 1H), 2.61(s, 3H) 第六步 'HNMR (400MHz, CDC1 3 ): 57.57 (dd, J=8.0, 1H), 7.24 (dd, J=8.0, 1H), 7.05 (t, J=8.0, 1H), 2.61(s, 3H) step
5-(2-羟基 -3-{N'-[3-甲基 -5-氧代小 (5,6,7,8-四氢萘 -2-基) -1，5-二氢吡唑 1-4-亚基] '-肼 基 苯 )-2-甲基呋喃 -3-羧酸 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo small (5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole 1-4-subunit] '-mercaptophenyl)-2-methylfuran-3-carboxylic acid
冰浴下将 5-(2-羟基 -3-氨基-苯基) -2-甲基呋喃 -3-羧酸氢溴酸盐 53e (200 mg, 0.64 mmol) 溶解于 2.2 mL IN盐酸中， 滴加入 0.9 mL亚硝酸钠溶液 (48 mg, 0.7 mmol), 反应 20分钟， 再加入 5-甲基 -2-(5,6，7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (131 mg, 0.57 mmol), 用饱和碳酸氢钠溶液调节 pH至 8， 加入 2 mL乙醇， 室温反 应过夜。 TLC跟踪至原料消失， 过滤， 固体加入到 20 mL水中， 再用浓盐酸调节
pH=3〜4， 过滤， 固体中加入 8 mL乙酸乙酯搅拌 1小时， 过滤， 所得固体干燥后 得到标题产物 5-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1 -(5,6,7,8-四氢萘 -2-基) -1 ,5-二氢吡唑 1-4-亚基] -肼基 苯) -2-甲基呋喃 -3-羧酸 53 (200 mg， 红色固体)。 产率： 73.8%。 1HNMR(400MHz, DMSO-c/6): δ 1.75(m, 4H), 2.3 l(s, 3H), 2.62(s, 3H), 2.77(m, 4H), 7.14(m, 3H)， 7.47(d, J=7.6Hz, I H), 7.65(m, 3H), 9.79(s, IH), 12.73(br, IH), 13.76(br, IH) 实施例 54 Dissolve 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide 53e (200 mg, 0.64 mmol) in 2.2 mL of IN hydrochloric acid under ice bath. Add 0.9 mL of sodium nitrite solution (48 mg, 0.7 mmol), react for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4- Dihydropyrazol-3-one 3i (131 mg, 0.57 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. TLC traces to disappearance of raw materials, filtration, solids added to 20 mL of water, and then adjusted with concentrated hydrochloric acid After filtration, the solid was added with 8 mL of ethyl acetate and stirred for 1 hour, filtered, and the obtained solid was dried to give the title product 5-(2-hydroxy-3-{N'-[3-methyl-5- Oxo-1 -(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole 1-4-ylidene]-mercaptophenyl)-2-methylfuran- 3-carboxylic acid 53 (200 mg, red solid). Yield: 73.8%. 1 HNMR (400MHz, DMSO-c / 6): δ 1.75 (m, 4H), 2.3 l (s, 3H), 2.62 (s, 3H), 2.77 (m, 4H), 7.14 (m, 3H), 7.47 (d, J = 7.6 Hz, IH), 7.65 (m, 3H), 9.79 (s, IH), 12.73 (br, IH), 13.76 (br, IH) Example 54
-(2-羟基- -W'-「3-甲基 -5-氧代- 1 -(5,6,7,8-四氢萘亚甲基 -2-基 I ：氢吡唑 -4-亚 基 肼基 苯基) -呋喃 -2-羧酸甲酯 -(2-hydroxy--W'-"3-methyl-5-oxo- 1 -(5,6,7,8-tetrahydronaphthalenylene-2-yl I:hydropyrazole-4- Methyl phenyl phenyl)-furan-2-carboxylate
5-(2-甲氧基 -3-硝基苯基) -呋喃 -2-羧酸甲酯 将 2-(2-甲氧基 -3-硝基苯基)- 4,4,5,5-四甲基 -[1，3，2]硼酸乙二醇酯 6a (3.6 g, 12 mmol), 5-溴 -呋喃 -2-羧酸甲酯 (2.05 g, 10 mmol), 四 (三苯基膦)钯 (1.55 g, 0.5 mmol) 和碳酸钠 C2.12 g, 20 nimoi;)溶解于 1 ,4-二氧六环中， 加热回流 3小时。 TLC跟踪至 原料消失， 过滤， 滤液减压浓缩， 向残余物中加入 30 mL水和 50 mL乙酸乙酯， 搅拌均匀后静置， 有机相浓缩后用乙酸乙酯和正己垸重结晶， 得到标题产物 5-(2- 甲氧基 -3-硝基苯基) -呋喃 -2-羧酸甲酯 54a(500 mg， 黄色固体)。 产率： 18%。 Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 2-(2-methoxy-3-nitrophenyl)-4,4,5,5 -Tetramethyl-[1,3,2]ethyl carbamate 6a (3.6 g, 12 mmol), methyl 5-bromo-furan-2-carboxylate (2.05 g, 10 mmol), tetrakis (triphenyl) Palladium (1.55 g, 0.5 mmol) and sodium carbonate C2.12 g, 20 nimoi;) were dissolved in 1,4-dioxane and heated to reflux for 3 hours. TLC was traced to the disappearance of the starting material, filtered, and the filtrate was concentrated under reduced pressure. To the residue, 30 mL of water and 50 mL of ethyl acetate were added, and the mixture was stirred and dried. The organic phase was concentrated and recrystallized from ethyl acetate and hexane to give title. Product 5-(2-Methoxy-3-nitrophenyl)-furan-2-carboxylic acid methyl ester 54a (500 mg, yellow solid). Yield: 18%.
'HNMR(400MHz, CDC13): δ 8.23(dd, J=7.6, IH), 7.83(dd, 5=7.6, IH), 7.35(m, 2H), 7.16(d, J=4.0, IH), 3.98(s, 3H), 3.94(s, 3H) 第二步 'HNMR (400MHz, CDC1 3 ): δ 8.23 (dd, J=7.6, IH), 7.83 (dd, 5=7.6, IH), 7.35 (m, 2H), 7.16 (d, J=4.0, IH), 3.98(s, 3H), 3.94(s, 3H) Step 2
氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸甲酯 Methylamino-2-methoxy-phenyl)-furan-2-carboxylate
将 5- (2-甲氧基 -3-硝基苯基) -呋喃 -2-羧酸甲酯 54a (500 mg, 1.8 mmol)溶解于甲 醇中， 再加入 50 mg钯 -碳， 于氢气氛下加热回流 4小时。 TLC跟踪至原料消失， 减压浓缩， 所得固体用乙酸乙酯和正己垸的混合溶剂重结晶 (V:V=1 :5)后干燥， 得 到标题产物 5-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸甲酯 54b(370 mg, 白色固体)， 产率： 83%。
第三步 Dissolve methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 54a (500 mg, 1.8 mmol) in methanol, then add 50 mg palladium-carbon to hydrogen atmosphere Heat under reflux for 4 hours. TLC was traced to the disappearance of the starting material, and the mixture was concentrated under reduced pressure. The obtained solid was recrystallized from a solvent mixture of ethyl acetate and n-hexane (V:V = 1:5) and dried to give the title product 5-(3-amino-2-methoxy Methyl-phenyl)-furan-2-carboxylate 54b (370 mg, white solid), Yield: 83%. third step
5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸甲酯 Methyl 5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylate
将 5-(3-氨基 -2-甲氧基-苯基) -呋喃 -2-羧酸甲酯 54b (350 mg, 1.42 mmol)溶解于 二氯甲烷中， 滴加入三溴化硼 (3.3 mL, 2.0 mol/L), 室温反应 2小时。 TLC跟踪至 原料消失， 用甲醇淬灭反应， 反应液用饱和碳酸氢钠溶液调节 pH至 5〜6， 用乙 酸乙酯萃取， 有机相浓缩后经柱层析得到标题产物 5- (3-氨基 -2-羟基苯基) -呋喃 -2- 羧酸甲酯 54c(170 mg， 灰色固体)。 产率： 451%。 Dissolve methyl 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylate 54b (350 mg, 1.42 mmol) in dichloromethane and add boron tribromide (3.3 mL) dropwise. , 2.0 mol/L), react at room temperature for 2 hours. The TLC was traced to the disappearance of the starting material, and the reaction was quenched with methanol. The reaction mixture was adjusted to pH 5 to 6 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. Methyl 2-hydroxyphenyl)-furan-2-carboxylate 54c (170 mg, m.p.). Yield: 451%.
MS m/z (ESI): 232.0[M-1] MS m/z (ESI): 232.0 [M-1]
!HNMR(400MHz, DMSO-i/6): 57.32(d, J=7.6, I H), 7.05(d, J=7.6， IH), 6.82(m, 3H), 3.96(s, 3H) " 第四步 ! HNMR (400MHz, DMSO-i / 6): 57.32 (d, J = 7.6, IH), 7.05 (d, J = 7.6, IH), 6.82 (m, 3H), 3.96 (s, 3H) " Fourth step
5-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -l-(5，6,7,8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚 基] -肼基 }-苯基) -呋喃 -2-羧酸甲酯 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5 -dihydropyrazole-4-ylidene]-mercapto}-phenyl)-furan-2-carboxylic acid methyl ester
冰浴下将 5-(3-氨基 -2-羟基苯基)-呋喃- 2-羧酸甲酯 54c (110 mg, 0.47 mmol)溶解 于盐酸 (1.6 mL, 1 mol/L)中， 滴加入 0.6 mL亚硝酸钠溶液 (36 mg, 0.52 mmol), 反应 10分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2，4-二氢吡唑 -3-酮 3i (97 mg, 0.43 mmol), 用饱和碳酸氢钠溶液调节 pH至 8〜9， 室温反应 24小时。 TLC跟踪至原 料消失， 过滤， 固体溶解于 15 mL水中， 冰浴下用浓盐酸调节 pH至 3〜4， 过滤， 固体经柱层析后干燥， 得到标题产物 5-(2-羟基 -3-{N'-[3-甲基 -5-氧代 -1 -(5,6,7,8-四 氢萘亚甲基 -2-基) -1 ,5-二氢吡唑 -4-亚基] -肼基 苯基) -呋喃 -2-羧酸甲酯 54(48 mg, 红色固体)。 产率： 23.9%。 Dissolve methyl 5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylate 54c (110 mg, 0.47 mmol) in hydrochloric acid (1.6 mL, 1 mol/L) under ice-cooling. 0.6 mL of sodium nitrite solution (36 mg, 0.52 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-di Hydropyrazol-3-one 3i (97 mg, 0.43 mmol) was adjusted to pH 8 to 9 with a saturated sodium hydrogen carbonate solution and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was dried by column chromatography to give the title product 5-(2-hydroxy-3- {N'-[3-methyl-5-oxo-1 -(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4-ya Methyl]-nonylphenyl)-furan-2-carboxylate 54 (48 mg, red solid). Yield: 23.9%.
MS m/z (ESI): 470.7[M-1] MS m/z (ESI): 470.7 [M-1]
'H MR(400MHz, DMSO- 6): δ 1.76(m, 4H), 2.31(s, 3H), 2.73(m, 4H), 3.86(s, 3H), 7.12(m, IH), 7.17(m, IH), 7.22(t, J=8.0Hz, IH), 7.46(m, IH), 7.56(m, I H), 7.65(m, 2H)， 7.72(m, IH), 10.02(s, IH), 13.72(br, IH) 实施例 55 'H MR(400MHz, DMSO-6): δ 1.76(m, 4H), 2.31(s, 3H), 2.73(m, 4H), 3.86(s, 3H), 7.12(m, IH), 7.17(m , IH), 7.22(t, J=8.0Hz, IH), 7.46(m, IH), 7.56(m, IH), 7.65(m, 2H), 7.72(m, IH), 10.02(s, IH) , 13.72(br, IH) Example 55
5-{2-羟基 -3-ΓΝ'-Π -茚满 -5-基 -3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基) -肼基 1-苯基 呋 5-{2-hydroxy-3-ΓΝ'-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- Phenylfur
冰浴下将 5-(3-氨基 -2-羟基苯基) -呋喃 -2-羧酸甲酯 54c (110 mg, 0.47 mmol)溶解 于盐酸 (1.6 mL, 1 mol/L)中， 滴加入 0.6 mL亚硝酸钠溶液 (36 mg, 0.52 mmol), 反应 20分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (91 mg, 0.43 mmol), 用 饱和碳酸氢钠溶液调节 pH至 8〜9， 室温反应 24小时。 TLC跟踪至原料消失， 用 乙醇淬 ^反应， 过滤， 固体溶解于 15 mL水中， 冰浴下用浓盐酸调节 pH至 3〜4， 过滤， 固体经柱层析后干燥， 得到标题产物 5-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲基 -5- 氧代 -1,5-二氢吡唑 -4-亚基)-肼基] -苯基 } -呋喃 -2-羧酸甲酯 55(137 mg, 红色固体)。 产率： 70.3%。 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L) and added dropwise. 0.6 mL of sodium nitrite solution (36 mg, 0.52 mmol), react for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (91 mg , 0.43 mmol), the pH was adjusted to 8-9 with a saturated sodium bicarbonate solution and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was dried by column chromatography to give the title product 5-- 2-hydroxy-3-[Ν'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-benzene Methyl 5-furan-2-carboxylate 55 (137 mg, red solid). Yield: 70.3%.
MS m/z (ESI): 456.7[M-1] MS m/z (ESI): 456.7 [M-1]
]HNMR(400MHz, DMSO-c/6): δ 2.05(m, 2H), 2.33(s, 3H), 2.89(m, 4H), 3.86(s, 3H), 7.18(m, 2H), 7.30(d, J=8.4Hz, 1H), 7.46(d, J=3.6Hz, 1H), 7.56(m, 1H), 7.71(m, 2H), 7.78(s, lH) ' 实施例 56 ] HNMR (400MHz, DMSO-c / 6): δ 2.05 (m, 2H), 2.33 (s, 3H), 2.89 (m, 4H), 3.86 (s, 3H), 7.18 (m, 2H), 7.30 ( d, J = 8.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.56 (m, 1H), 7.71 (m, 2H), 7.78 (s, lH) 'Example 56
3WN'-「l-(2,2-二甲基茚满 -5-基) -3-甲基 -5-氧代- 1,5-二氢吡唑 -4-亚基 肼基 }-2'-羟基 3WN'-"l-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene}}-2 '-hydroxyl
联苯 -3-羧酸 Biphenyl-3-carboxylic acid
冰浴下将 2'-羟基 -3'-氨基联苯基 -3-羧酸氢溴酸盐 If (150 mg, 0.5 mmol)溶解于 Dissolving 2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid hydrobromide If (150 mg, 0.5 mmol) in an ice bath
-盐酸 (1.7 mL, 1 mol/L)中，滴加入 0.6 mL亚硝酸钠溶液 (38 mg, 0.55 mmol),反应 20 分钟，再加入 2-(2,2-二甲基茚满- 5-基) -5-甲基 -2,4-二氢吡唑 -3-酮 45d (109 mg， 0.45 mmol), 用饱和碳酸氢钠溶液调节 pH至 8〜9, 用乙醇淬灭气泡， 室温反应过夜。 TLC跟踪至原料消失， 过滤， 固体加入 15 mL水， 用浓盐酸调节 pH值至 3〜4， 过滤，滤饼用乙酸乙酯洗涤 (1 mLx3)后干燥得到标题产物 3'-{Ν'-[1-(2,2-二甲基茚满 -5-基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -肼基 }-2'-羟基联苯 -3-羧酸 56(16 mg,黄 色固体)， 产率： 7.6%。 ' MS m/z (ESI): 480.7[M-1]
'HNMR(400MHz, DMSO-d6): 61 .13(s,6H), 2.32(s,3H), 2.70(m,4H), 7.14(m,2H). - Hydrochloric acid (1.7 mL, 1 mol/L), add 0.6 mL of sodium nitrite solution (38 mg, 0.55 mmol), react for 20 minutes, then add 2-(2,2-dimethylindane- 5- -5-Methyl-2,4-dihydropyrazol-3-one 45d (109 mg, 0.45 mmol), adjusted to pH 8~9 with saturated sodium bicarbonate solution, quenched with ethanol, and reacted at room temperature overnight. The TLC was traced to disappearance of the starting material, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1 mL×3) and dried to give the title product 3'-{Ν'- [1-(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]-indenyl}-2' -Hydroxybiphenyl-3-carboxylic acid 56 (16 mg, yellow solid), Yield: 7.6%. ' MS m/z (ESI): 480.7 [M-1] 'HNMR (400MHz, DMSO-d 6 ): 61.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 (m, 2H).
7.22(d,J=8.8Hz, lH), 7.61 (t,J=8.0Hz,lH), 7.66(d,J=7.6Hz, lH), 7.70(m,2H), 7.22 (d, J = 8.8 Hz, lH), 7.61 (t, J = 8.0 Hz, lH), 7.66 (d, J = 7.6 Hz, lH), 7.70 (m, 2H),
7.80(d,J=7.6Hz, lH), 7.95(d,J=8.0Hz, lH),8.13(s,lH) 实施例 57 7.80 (d, J = 7.6 Hz, lH), 7.95 (d, J = 8.0 Hz, lH), 8.13 (s, lH) Example 57
4-(2-羟基 -3-{N'-「3-甲基 -5-氧代 -l-(5,6,7，8-四氢萘亚甲基 - 2-基)- ：氢吡唑 -4-亚 基卜肼基 苯 1H-吡咯- 2-羧酸 4-(2-hydroxy-3-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-:hydropyridyl Azole-4-ylidenebenylbenzene 1H-pyrrole-2-carboxylic acid
第一步 First step
2,2,2-三氯 - 1 -( 1 H-吡咯 -2-基) -乙酰 2,2,2-trichloro-1 -( 1 H-pyrrol-2-yl)-acetyl
将三氯乙酰氯 (45 g， 247 mmol)溶解于 100 mL乙醚中，将吡咯（15.4 g， 230 mmol) 溶解于 100 mL中，滴加到上述溶液中，加入 200 mL碳酸钾溶液 (20 g, 145 mmol), 加毕室温搅拌 1 小时， TLC监测反应至原料反应完全， 反应液分液， 有机相用无 水硫酸镁干燥， 过滤除去干释剂， 滤液减压浓缩后柱层析得到标题产物 2,2,2-三氯 - 1 -(1Η-吡咯 -2-基) -乙酰 57b(38 g， 白色固体)， 产率： 77.8%。 Dissolve trichloroacetyl chloride (45 g, 247 mmol) in 100 mL of diethyl ether, dissolve pyrrole (15.4 g, 230 mmol) in 100 mL, add dropwise to the above solution, and add 200 mL of potassium carbonate solution (20 g). , 145 mmol), and stirred at room temperature for 1 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was separated. The organic phase was dried over anhydrous magnesium sulfate and filtered and evaporated to dryness. Product 2,2,2-Trichloro-1 -(1Η-pyrrol-2-yl)-acetyl 57b (38 g, white solid), Yield: 77.8%.
MS m/z (ESI): 210.3 [M-1] 第二步 MS m/z (ESI): 210.3 [M-1] Step 2
2,2,2-三氯 - 1-(4-碘 -1H-吡咯 -2-基) -乙酰 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetyl
将 2,2,2-三氯 -1- (1 H-吡咯 -2-基) -乙酰 57b(32 g, 151.8 mmol)溶解于 250 mL二 氯甲垸中， 将氯化碘 (25 g， 153 mmol)溶解于 125 mL二氯甲垸中， 滴加到上述溶 液中， 加毕室温搅拌 2小时， TLC监测反应至原料反应完全， 反应液依次用饱和 碳酸钠溶液、 硫代硫酸钠溶液 (2M)和饱和食盐水洗涤， 用无水硫酸镁千燥， 过滤 除去干燥剂， 滤液减压浓缩后柱层析得到标题产物 2,2,2-三氯 -1 -(4-碘 -1 H-吡咯 -2- 基) -乙酰 57c(47 g， 黄色固体)， 产率： 92%。 Dissolve 2,2,2-trichloro-1-(1 H-pyrrol-2-yl)-acetyl 57b (32 g, 151.8 mmol) in 250 mL of dichloromethane, iodine chloride (25 g, 153 mmol) was dissolved in 125 mL of dichloromethane, added dropwise to the above solution, and stirred at room temperature for 2 hours. The reaction was monitored by TLC until the reaction of the starting material was complete. The reaction solution was sequentially saturated sodium carbonate solution and sodium thiosulfate solution ( 2M) Washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the filtrate was concentrated under reduced pressure to give the title product 2,2,2-trichloro-1 -(4-iodo-1 H -pyrrol-2-yl)-acetyl 57c (47 g, yellow solid), Yield: 92%.
MS m/z (ESI): 336.4[M-1]
第三步 MS m/z (ESI): 336.4 [M-1] third step
4-碘 -1H-吡咯 -2-羧酸甲酯 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester
将 2,2,2-三氯 -1-(4-碘 -1H-吡咯 -2-基)-乙酰 57c(47 g， 136 mmol)溶解于 265 mL 甲醇中， 将甲醇钠 (17.23 g， 163 mmol)溶解于 200 mL甲醇中， 滴加到上述溶液中， 室温搅拌 1小时， TLC监测反应至原料反应完全， 反应液减压浓缩， 残余物中加 入 20 mL水， 用乙酸乙酯萃取 (30 mLx3)， 合并有机相， 有机相用饱和食盐水洗涤， 用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得到标题产物 4-碘 -1H-吡咯 -2- 羧酸甲酯 57d(32.2 g， 灰色固体)， 产率： 92.5%。 Dissolve 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetyl 57c (47 g, 136 mmol) in 265 mL of methanol, sodium methoxide (17.23 g, 163 Methyl acetate was dissolved in 200 mL of methanol, added dropwise to the above solution, and stirred at room temperature for 1 hour. The reaction was monitored by TLC until the reaction mixture was completed. The mixture was concentrated under reduced pressure. The organic phase was combined, and the organic layer was washed with brine, dried over anhydrous sodium sulfate 32.2 g, gray solid), Yield: 92.5%.
MS m/z (ESI): 250.1 [M-1] 第四步 MS m/z (ESI): 250.1 [M-1] Step 4
4-碘— 1 -(甲苯 -4-磺酰 )- 1 H-吡咯 -2-羧酸甲酯 将 4-碘 -1H-吡咯 -2-羧酸甲酯 57d(25.1 g, 100 mmol)溶解于 150 mL二氯甲垸中， 加入三乙胺 (30.6 mL， 220 mmol)、 4-二甲氨基吡啶（1.22 g， 10 mmol)和对甲苯磺酸 (21 g, 110 mmol),于 20°C下反应过夜， TLC监测反应至原料反应完全，加入 30 mL 盐酸 (IN)淬灭反应。 反应液用二氯甲垸萃取 (50 mLx3), 有机相依次用饱和碳酸钠 溶液、 饱和食盐水洗涤， 用无水硫酸钠干燥， 过滤除去干燥剂， 滤液减压浓缩后 柱层析得到标题产物 4-碘 -1- (甲苯 -4-磺酰) -1H-吡咯 -2-羧酸甲酯 57e(32.5 g， 白色固 体)， 产率： 80.2%。 Methyl 4-iodo-1-(toluene-4-sulfonyl)- 1 H-pyrrole-2-carboxylate Methyl 4-iodo-1H-pyrrole-2-carboxylate 57d (25.1 g, 100 mmol) In 150 mL of dichloromethane, triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g, 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol) at 20 ° The reaction was carried out overnight at C, and the reaction was monitored by TLC until the starting material was completely reacted, and the reaction was quenched by the addition of 30 mL of hydrochloric acid (IN). The reaction mixture was extracted with methylene chloride (50 mL×3). The organic phase was washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, white solid), yield: 80.2%.
MS m/z (ESI): 405.8[M+1] 第五步 MS m/z (ESI): 405.8 [M+1] Step 5
4-(3 -硝基 -2-甲氧基 -苯基 )- 1 - (甲苯 -4-磺酰) - 1 H-吡咯 -2-羧酸甲酯 将 2-(2-甲氧基 -3-硝基苯基) -4,4,5,5-四甲基 -[1,3,2]硼酸乙二醇酯 6a(2.05 g， 5.5 、 4-碘- （甲苯-4-磺酰)-111-吡咯-2-羧酸甲酯 57e(2.03 g， 5 mmol)、碳酸钾（1.38 g， 10 mmol)和四 (苯基膦)钯 (144 mg， 0.125 mmol)加入到 15 mLl,4-二氧六环和 5 mL 水的混合溶剂中， 加毕于 8(TC微波反应 30分钟， TLC监测反应原料反应完全， 反 应液减压浓缩， 加入 20 mL水， 搅拌均匀后用乙酸乙酯萃取 (20 mLX3)， 合并有机 相， 有机相用饱和食盐水洗涤， 无水硫酸镁干燥， 过滤除去干燥剂， 滤液减压浓 缩后柱层析得到标题产物 4-(3-硝基- 2-甲氧基 -苯基 )-1- (甲苯 -4-磺酰) -1H-吡咯 -2-羧 酸甲酯 57f(1.04 g， 灰色固体)， 产率： 48%。 Methyl 4-(3-nitro-2-methoxy-phenyl)- 1 -(toluene-4-sulfonyl)-1 H-pyrrole-2-carboxylate 2-(2-methoxy- 3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (2.05 g, 5.5, 4-iodo-(toluene-4-sulfonyl) -111-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(phenylphosphine)palladium (144 mg, 0.125 mmol) were added to 15 mLl. In a mixed solvent of 4-dioxane and 5 mL of water, add 8 (TC microwave reaction for 30 minutes, TLC monitor the reaction material to complete reaction, concentrate the reaction under reduced pressure, add 20 mL of water, stir evenly and use acetic acid The ester was extracted (20 mL×3), and the organic layer was combined, evaporated, evaporated, evaporated, evaporated Methyl-methoxy-phenyl)-1-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylate 57f (1.04 g, m.p.).
MS m/z (ESI): 431.0[M+1] MS m/z (ESI): 431.0 [M+1]
'HNMR(400MHz, CDC13): δ 8.225-8.23 l(m, 1Η), 7.979~8.00(m, 2H), 7.710~7.765(m, 1H), 7.452~7.457(m, 1H), 7.389~7.409(m, 2H), 7.271~7.311(m, 2H), 3.839(s, 3H), 3.829(s, 2H), 2.488(s, 3H) 第六步
4-(3-硝基 -2-甲氧基-苯基) - 1 H-吡咯 -2-羧酸 'HNMR (400MHz, CDC1 3 ): δ 8.225-8.23 l(m, 1Η), 7.979~8.00(m, 2H), 7.710~7.765(m, 1H), 7.452~7.457(m, 1H), 7.389~7.409 (m, 2H), 7.271~7.311(m, 2H), 3.839(s, 3H), 3.829(s, 2H), 2.488(s, 3H) Step 6 4-(3-nitro-2-methoxy-phenyl)-1 H-pyrrole-2-carboxylic acid
将 4-(3-硝基 -2-甲氧基 -苯基 )-1- (甲苯 -4-磺酰) -1H-吡咯 -2-羧酸甲酯 57f(1.04 g， 2.42 mmol)和一水合氢氧化锂 (1.01 g, 24.19 mmol)加入到 10 mL N,N-二甲基甲酰胺 和 5 mL水的混合溶剂中， 于 100°C微波反应 30分钟， TLC监测反应原料反应完 全， 反应液用盐酸 (IN)调节 pH至 3， 有大量固体析出， 过滤， 滤饼干燥后得到标 题产物 4-(3-硝基 -2-甲氧基-苯基) -1H-吡咯 -2-羧酸 57g(350 mg， 黄色固体)， 产率： 50%。 4-(3-Nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, 2.42 mmol) and one Lithium hydroxide hydrate (1.01 g, 24.19 mmol) was added to a mixed solvent of 10 mL of N,N-dimethylformamide and 5 mL of water, and microwaved at 100 ° C for 30 minutes. The reaction of the reaction was completed by TLC. The liquid was adjusted to pH 3 with hydrochloric acid (IN), a large amount of solid was precipitated, filtered, and the filter cake was dried to give the title product 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylate. Acid 57 g (350 mg, yellow solid), Yield: 50%.
S m/z (ESI): 260.8[M-1] 第七步 S m/z (ESI): 260.8 [M-1] Step 7
4-(3-氨基 -2-甲氧基-苯基) -1H-吡咯 -2-羧酸 将 4-(3-硝基 -2-甲氧基-苯基) -1H-吡咯 -2-羧酸 57g(633 mg， 2.41 mmol)溶解于 15 mL乙酸乙酯中， 加入 127 mg钯 /碳和甲酸胺 (609 mg， 9.66 mmol), 加毕加热回 流 2小时， TLC监测反应至原料反应完全， 反应过滤除去钯 /碳， 滤液减压浓缩后 柱层析得到标题产物 4-(3-氨基 -2-甲氧基-苯基) -1H-吡咯 -2-羧酸 57h(130 mg， 灰色 固体)， 产率： 23.2%。 4-(3-Nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2- The carboxylic acid 57 g (633 mg, 2.41 mmol) was dissolved in 15 mL of ethyl acetate. 127 mg of palladium/carbon and ethyl formate (609 mg, 9.66 mmol) were added, and the mixture was heated and refluxed for 2 hours, and the reaction was monitored by TLC. Completely, the reaction was filtered to remove the palladium/carbon. The filtrate was concentrated under reduced pressure and then purified to give the title product 4-(3-amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130 mg, Gray solid), Yield: 23.2%.
MS m/z (ESl): 230.8[M-1] MS m/z (ESl): 230.8 [M-1]
'HNMR(400MHz, DMSO- 6): δ 11.631(s, 1H), 7.305(s, 1H), 7.025(s, 1H), 'HNMR (400MHz, DMSO-6): δ 11.631(s, 1H), 7.305(s, 1H), 7.025(s, 1H),
6.712~6.798(m, 2H), 6.524-6.543 (m, 1H), 3.514(s, 3H) 第八歩 6.712~6.798(m, 2H), 6.524-6.543 (m, 1H), 3.514(s, 3H)
4-(3-氨基 -2-羟基苯基 1H-吡咯 -2-羧酸 4-(3-Amino-2-hydroxyphenyl 1H-pyrrole-2-carboxylic acid
将 4-(3-氨基 -2-甲氧基-苯基) -1H-吡咯 -2-羧酸 57h(130 mg， 0.56 mmol)加入 2 mL 二氯甲垸中， 加入溴化硼 (1.12 mL， 2.24 mmol), 室温搅拌 6小时， TLC监测反应 至原料反应完全， 用甲醇淬灭反应， 反应液减压浓缩后柱层析得到标题产物 4-(3- 氨基- 2-羟基苯基) -1H-吡咯 -2-羧酸 57i(140 mg， 灰色固体)， 产率： 99%。 Add 4-(3-amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130 mg, 0.56 mmol) to 2 mL of dichloromethane and add boron bromide (1.12 mL) , 2.24 mmol), stirring at room temperature for 6 hours, the reaction was monitored by TLC until the reaction mixture was completed, and the reaction was quenched with methanol, and the reaction mixture was concentrated under reduced pressure to give the title product 4-(3-amino-2-hydroxyphenyl) 1H-pyrrole-2-carboxylic acid 57i (140 mg, gray solid), Yield: 99%.
'HNMR(400MHz, CD3OD): 5 7.312(s, 1H), 7.178(s, 1H), 7.006~7.028(m, 1H), 6.822~6.837(m, 2H) 第九歩 'HNMR (400MHz, CD 3 OD): 5 7.312(s, 1H), 7.178(s, 1H), 7.006~7.028(m, 1H), 6.822~6.837(m, 2H)
4-(2-羟基 -3-{N'-[3-甲基 -5-氧代小(5,6,7,8-四氢萘亚甲基 -2-基) -1,5-二氢吡唑 -4-亚 基] -肼基 } -苯) -1H-吡咯 -2-羧酸 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo small (5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-mercapto}-phenyl)-1H-pyrrole-2-carboxylic acid
冰浴下将 4-(3-氨基 -2-羟基苯基) -1H-吡咯 -2-羧酸 57i (130 mg, 0.43 mmol)溶解 于盐酸 (1.5 mL, 1 mol/L)中， 滴加入 0.6 mL亚硝酸钠溶液 (33 mg, 0.47 mmol), 反应 10分钟， 再加入 5-甲基 -2-(5,6,7,8-四氢萘 -2-基) -2,4-二氢吡唑 -3-酮 3i (89 mg, 0.3 mmol), 用饱和碳酸氢钠溶液调节 pH至 8〜9， 室温反应 24小时。 TLC跟踪至原 料消失， 过滤， 固体溶解于 15 mL水中， 冰浴下用浓盐酸调节 pH至 3〜4， 过滤，
滤饼用乙酸乙酯洗涤后干燥， 得到标题产物 4-(2-羟基 -3-{Ν'- [3-甲基 -5-氧代 -1- (5,6,7,8-四氢萘亚甲基 -2-基) -1 ,5-二氢吡唑 -4-亚基] -肼基 苯) -1Η-吡咯 -2-羧酸 57(38 mg, 灰色固体)。 产率： 21.3%。 4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (130 mg, 0.43 mmol) was dissolved in hydrochloric acid (1.5 mL, 1 mol/L). 0.6 mL of sodium nitrite solution (33 mg, 0.47 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-di Hydropyrazol-3-one 3i (89 mg, 0.3 mmol) was adjusted to pH 8~9 with saturated sodium bicarbonate solution and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, and filtered. The filter cake was washed with ethyl acetate and dried to give the title product 4-(2-hydroxy-3-{Ν'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro) Naphthylmethyl-2-yl)-1,5-dihydropyrazole-4-ylidene]-mercaptophenyl)-l-pyrrole-2-carboxylic acid 57 (38 mg, m.p.). Yield: 21.3%.
'HNMR(400MHz, DMSO- (5): δ 11.74(1 H,br), 11.64(lH,br), 7.60(lH,d J=8.2), 7.49(lH,d J=8.0), 7.32(3H,m), 7.05(3H,m), 2.67(4H,m), 1.95(3H,s ), 1.13(4H,m) 实施例 58 'HNMR (400 MHz, DMSO-(5): δ 11.74 (1H, br), 11.64 (1H, br), 7.60 (1H, d J = 8.2), 7.49 (lH, d J = 8.0), 7.32 (3H , m), 7.05 (3H, m), 2.67 (4H, m), 1.95 (3H, s), 1.13 (4H, m) Example 58
4-{2-羟基 -3-ΓΝ'-Π -茚满 -5-基 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基 1-苯 1H-吡 4-{2-hydroxy-3-ΓΝ'-Π-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl 1- Benzene 1H-pyridyl
冰浴下将 4-(3-氨基 -2-羟基苯基) -1H-吡咯 -2-羧酸 57i (240 mg, 0.8 mmol)溶解于 盐酸 (3 mL, 1 mol/L)中， 滴加入 1.1 mL亚硝酸钠溶液 (61 mg, 0.88 mmol), 反应 20 分钟， 再加入 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 li (154 mg, 0.72 mmol), 用饱 和碳酸氢钠溶液调节 pH至 8〜9， 室温反应 24小时。 TLC跟踪至原料消失， 用乙 醇淬灭反应， 过滤， 固体溶解于 15 mL水中， 冰浴下用浓盐酸调节 pH至 3〜4， 过滤， 固体经柱层析后干燥， 得到标题产物 4-{2-羟基 -3-[Ν'-(1-茚满 -5-基 -3-甲基 -5- 氧代 -1 ,5-二氢吡唑 -4-亚基) -肼基]-苯}-1?1-吡咯 -2-羧酸 58(101 mg,红色固体)，产率： 28.4%。 4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (240 mg, 0.8 mmol) was dissolved in hydrochloric acid (3 mL, 1 mol/L). 1.1 mL of sodium nitrite solution (61 mg, 0.88 mmol), reaction for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (154 mg , 0.72 mmol), the pH was adjusted to 8-9 with a saturated sodium hydrogen carbonate solution and allowed to react at room temperature for 24 hours. TLC was traced to disappearance of the starting material, the reaction was quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was dried by column chromatography to give the title product 4-{ 2-hydroxy-3-[Ν'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-benzene }-1?1-pyrrole-2-carboxylic acid 58 (101 mg, red solid), yield: 28.4%.
'HNMR(400MHz, DMSO- 6): 611.83(lH,br), 11.77(lH,br), 7.57(lH,d ,J=7.2),'HNMR (400MHz, DMSO-6): 611.83 (lH, br), 11.77 (lH, br), 7.57 (lH, d, J = 7.2),
7.50(lH,s), 7.37(4H,m), 7.26(1 H,m), 7.10(lH,m), 2.87(4H,m), 2.32(3H,s), 2.04(2H,m) 7.50(lH,s), 7.37(4H,m), 7.26(1 H,m), 7.10(lH,m), 2.87(4H,m), 2.32(3H,s), 2.04(2H,m)
测试例： Test case:
生物学评价 Biological evaluation
测试例 1 TPO系列化合物对 BAF3-TPOR细胞的增殖作用 Test Example 1 Proliferation of BAF3-TPOR cells by TPO series compounds
1. 材料和方法： 1. Materials and methods:
a. RPM1 Medium 1640,Powder,10* lL, 含 HEPES (Gibco Catalog no.23400021) b. FBS胎牛血清 （Gibco Catalog no.10099-141 )
、' υ A c. PENICILLIN STREPTOMYCIN SOL ( Gibco Catalog no. 15140-122 ) a. RPM1 Medium 1640, Powder, 10* lL, containing HEPES (Gibco Catalog no. 23400021) b. FBS fetal bovine serum (Gibco Catalog no.10099-141) , ' υ A c. PENICILLIN STREPTOMYCIN SOL ( Gibco Catalog no. 15140-122 )
d. Geneticin(G418) ( Gibco Catalog no, 11811 -098 ) d. Geneticin(G418) ( Gibco Catalog no, 11811 -098 )
e. recombinant mouse IL-3 (chemicon Catalog no.IL015 ) e. recombinant mouse IL-3 (chemicon Catalog no.IL015 )
f. Human Thrombopoietin R Mab ( TPO ) ( R&D Catalog no.MAB 1016 ) f. Human Thrombopoietin R Mab ( TPO ) ( R&D Catalog no.MAB 1016 )
g. DMSO (AppliChem Catalog no.A3672 ) g. DMSO (AppliChem Catalog no.A3672 )
h. QuikChange® Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515) i, Cell Counting Kit-8 (同仁化学研究所 Catalog no.CK04-13 ) h. QuikChange® Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515) i, Cell Counting Kit-8 (Tongren Chemical Research Institute Catalog no.CK04-13 )
j, Ba/F3细胞 (协和细胞库 Catalog no.0095) j, Ba/F3 cells (Concord Cell Bank Catalog no.0095)
k. EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control) k. EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control)
1. EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02) 1. EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02)
2. 操作步骤： 2. Operation steps:
(1) 质粒构建：根据 Entrez Gene ID:4325, Refseq: NM— 005373提供的 TPOR基因序 列，对购买的 EX-B0010-M02质粒（FulenGen)利用 QuikChange® Multi Site Directed Mutagenesis Kit (Stratagene)试剂盒进行 2点突变。多点突变引物序列分别为： g491a: 5'-gggaacttcagatcagctgggaggagccg-3 ' , g491a— antisense: (1) Plasmid construction: Purchasing the EX-B0010-M02 plasmid (FulenGen) using the QuikChange® Multi Site Directed Mutagenesis Kit (Stratagene) kit according to the TPOR gene sequence provided by Entrez Gene ID: 4325, Refseq: NM-005373 2 point mutation. The multi-point mutation primer sequences are: g491a: 5'-gggaacttcagatcagctgggaggagccg-3 ' , g491a- antisense:
5 '-cggctcctcccagctgatctgaagttccc-3 '； c965t: 5'-caggaccatgctagctcccaaggcttcttct-3', c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3，。 突变后质粒转化大肠杆菌 . DH5ot， 经 Amp 筛选出阳性克隆， 测序鉴定突变结果正确。 5 '-cggctcctcccagctgatctgaagttccc-3 '; c965t: 5'-caggaccatgctagctcccaaggcttcttct-3', c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3,. After the mutation, the plasmid was transformed into Escherichia coli. DH5ot, positive clones were screened by Amp, and the mutation results were confirmed by sequencing.
(2) BAF3-TPOR细胞株构建： 构建稳定高表达功能性 TPO受体的 BaF3细胞株。 将经 2点突变后的表达人 TPO受体和筛选基因 neomycin的 EX-B0010-M02质粒 ； 25μβ转染野生型 BaF3细胞 （ 1X107 ), 转染所用仪器为 Electro Square Porator ECM830 (BTX Division of Genetronic, Inc.US), 转染条件为： 250V, 18ms。通过 G418 ( Gibco, US ) 筛选获得 BAF3- TPOR稳定细胞株。 BAF3-TPOR在 RPMI1640 ( Gibco, US ) 培养基， 10%FB ( Gibco, US ) S， 800ng/ml G418, 5ng/mU rmIL-3 (Chemicon, US ) 中培养。 (2) Construction of BAF3-TPOR cell line: A BaF3 cell line stably expressing a highly functional TPO receptor was constructed. The by expressing human after the 2-point mutant TPO receptor and screening gene neomycin the EX-B0010-M02 plasmid; 25μ β transfected with wild-type BaF3 cells (1X10 7), transfection instruments as Electro Square Porator ECM830 (BTX Division of Genetronic, Inc. US), transfection conditions: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR was cultured in RPMI 1640 (Gibco, US) medium, 10% FB (Gibco, US) S, 800 ng/ml G418, 5 ng/mU rmIL-3 (Chemicon, US).
3. 化合物筛选： 3. Compound screening:
(1) 离心清洗细胞： 取适量细胞悬液 lOOOrpm,离心 5分钟， 弃去上清， 再用 10ml 不含 IL3的细胞培养液将细胞重新悬起， lOOOrpm,离心 5分钟， 弃去上清； (1) Centrifuge the cells by centrifugation: Take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 ml of cell culture medium containing no IL3, centrifuge at lOOOOrpm for 5 minutes, discard the supernatant;
(2) 加入 lml不含 IL3的细胞培养液将细胞吹打均匀，取适量细胞悬液稀释后计数； (2) Add 1 ml of cell culture medium containing no IL3 and evenly blow the cells, and take appropriate amount of cell suspension to dilute and count;
(3) 根据细胞计数结果制备密度为 100000个 /ml的细胞悬液； (3) preparing a cell suspension having a density of 100,000 /ml based on the cell count result;
(4) 于 96-well平板中每孔加入 ΙΟΟμΙ细胞悬液， 设置 3个复孔， 并设置空白对照 组 (Β)， 阴性对照组 (N)， TPO阳性对照组 (P)和待测化合物组 (S); (4) Add ΙΟΟμΙ cell suspension to each well of 96-well plate, set up 3 duplicate wells, and set blank control group (Β), negative control group (N), TPO positive control group (P) and test compound Group (S);
(5) 用 DMSO将待测化合物粉末配成 10mM的储存液， 再用 RPM11640稀释成不 同浓度： 30μΜ,10μΜ,3μΜ, ΙμΜ, 0.3μΜ， 0· 1μΜ,0.03μΜ, 0·01μΜ, 0.003μΜ, (5) The test compound powder was formulated into 10 mM stock solution in DMSO, and diluted to different concentrations with RPM11640: 30 μΜ, 10 μΜ, 3 μΜ, ΙμΜ, 0.3 μΜ, 0·1 μΜ, 0.03 μΜ, 0·01 μΜ, 0.003 μΜ,
0.001 μΜ;
(6) 每孔加入 ΙΟμΙ相应浓度的药液， 阳性对照孔中加入 l^ rhTPO(l(^g/mL); 0.001 μΜ; (6) Add ΙΟμΙ corresponding concentration of the drug solution to each well, and add l^ rhTPO (l(^g/mL) to the positive control well ;
(7) 置于 5%C02,37°C细胞培养箱中培养 24小时； (7) placed in a 5% CO 2, 37 ° C cell culture incubator for 24 hours;
(8) 每孔加入 l(^lCCK-8， 于细胞培养箱中培养 4小时； (8) Add l(^lCCK-8) to each well for 4 hours in a cell culture incubator;
(9) 利用 VICTOR3 (Perkin Elmer 1420-120)仪器在 450nm检测 OD值。 (9) The OD value was measured at 450 nm using a VICTOR3 (Perkin Elmer 1420-120) instrument.
4. 结果分析计算： 4. Analysis of results:
(1 ) 增值率定义： [(S- B)/(P-B)] *100% (1) Definition of value-added rate: [(S- B)/(P-B)] *100%
S: 样品； B: 空白对照； P: 阳性对照 S: sample; B: blank control; P: positive control
(2) 通过 Origin 7.0计算 EC50. (2) Calculate the EC 50 by Origin 7.0.
5. 结果： 5. Results:
化合物 TPO活性 £^0值 Compound TPO activity £^ 0 value
药物动力学测试 测试例 1 本发明化合的药代动力学测试
试验目的 Pharmacokinetic test test example 1 Pharmacokinetic test of the present invention Test purposes
以大鼠为受试动物， 应用 LC/MS/MS法测定了大鼠分别灌胃给予实施例 1、 实施 例 15和实施例 29后不同时刻血浆中的药物浓度。 研究本发明化合物在大鼠体内的 药代动力学行为， 评价其药动学特征。 Rats were used as test animals, and the concentration of the drug in plasma was measured by LC/MS/MS method at different times after administration of Example 1, Example 15 and Example 29 by intragastric administration. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
2、 试验方案 2. Test plan
2.1、 试验药品 2.1, test drugs
实施例 1、 实施例 15和实施例 29 Example 1, Example 15 and Example 29
2.2、 试验动物 2.2, test animals
健康成年 SD大鼠 24只， 雌雄各半， 购自上海西普尔 -必凯实验动物有限公司， 动物生产许可证号： SCXK (沪) 2003- 0002。 Healthy adult SD rats, 24 males and females, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2003-0002.
2.3、 仪器设备 2.3, equipment
TSQ Quantum Ultra AM三重四极杆质谱仪， 美国 Thermo Finnigan公司； Agilent 1200高效液相色谱系统， 美国 Agilent公司。 TSQ Quantum Ultra AM Triple Quadrupole Mass Spectrometer, Thermo Finnigan, USA; Agilent 1200 High Performance Liquid Chromatography System, Agilent, USA.
2.4、 药物配制 2.4, drug preparation
称取适量样品加 1%羧甲基纤维素钠制成 0.5 mg/ml (以原形计)混悬液， 临用时 配制。 An appropriate amount of the sample was weighed and added with 1% sodium carboxymethylcellulose to prepare a 0.5 mg/ml (as prototype) suspension, which was prepared at the time of use.
2.5、 给药 2.5, administration
健康成年 SD大鼠 24只， 雌雄各半， 平均分成 5组， 禁食过夜后分别灌胃给药， 给药剂量均为 5.0 mg/kg (以原形计)， 给药体积 10 ml/kg。 Twenty-four healthy adult SD rats, half male and half female, were divided into 5 groups. They were intragastrically administered overnight after fasting, and the dose was 5.0 mg/kg (in original form), and the dosage volume was 10 ml/kg.
2.6、 样品采集 2.6, sample collection
SD大鼠 24只， 雌雄各半， 禁食一夜后灌胃给药， 剂量为 5 mg/kg。 于给药前 及给药后 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 11.0, 14.0, 24.0, 36.0, 48.0 h由眼眶采血 0.2 ml, 置于肝素化试管中， 3500 rpm离心 lO min分离血浆， 子 20°C保存。 Twenty-four SD rats, half male and half female, were intragastrically administered overnight after fasting at a dose of 5 mg/kg. Before administration and after administration 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 11.0, 14.0, 24.0, 36.0, 48.0 h, 0.2 ml of blood was collected from the eyelids, placed in heparinized tubes, centrifuged at 3500 rpm. The plasma was separated by lO min and stored at 20 °C.
2.7、 分析方法 2.7, analytical methods
取给药后各时刻的大鼠血浆 50 μ1， 加入内标溶液 20 μ1， 甲醇： 水 (80: 20, ν/ν) Take 50 μl of rat plasma at each time after administration, add internal standard solution 20 μl, methanol: water (80: 20, ν/ν)
20 μΐ, 混匀后加入甲醇 150μΓ沉淀蛋白， 涡流混合 1 min， 13000 rpm离心 10 min， 取 20 μΐ 进行 LC/MS/MS分析。 After 20 μΐ, mix and add 150 μl of precipitated protein to methanol, vortex for 1 min, centrifuge at 13,000 rpm for 10 min, and take 20 μΐ for LC/MS/MS analysis.
2.8、 标准曲线制备 2.8, standard curve preparation
取大鼠空白血浆 50μ1，分别加入标准系列溶液，使血药浓度为 1.0, 5.0, 25.0, 50.0, 100.0, 250.0, 500.0 ng/ml, 加入内标溶液 20μ1， 按"血浆样品预处理"项下进行操作。 以血药浓度为横坐标， 样品与内标色谱峰面积比为纵坐标， 以加权最小二乘法 (w=l/x2)进行线性回归， 获得典型标准曲线方程。 Take 50μ1 of rat blank plasma and add the standard series solution to make the blood concentration 1.0, 5.0, 25.0, 50.0, 100.0, 250.0, 500.0 ng/ml, add the internal standard solution 20μ1, press the "plasma sample pretreatment" Take action. Taking the plasma concentration as the abscissa, the ratio of the peak area of the sample to the internal standard is the ordinate, and the linear regression is performed by the weighted least squares method (w=l/x 2 ) to obtain the typical standard curve equation.
2.9、 药代动力学参数计算
对受试化合物的药代动力学行为进行房室模型拟合， 并计算主要药代动力学 参数， 其中 Cmax、 tmax采用实测值。 2.9, calculation of pharmacokinetic parameters The pharmacokinetic behavior of the test compound was fitted to the atrioventricular model, and the main pharmacokinetic parameters were calculated, wherein C max and t max were measured.
3、 药代动力学参数结果 3, pharmacokinetic parameters results
本发明化合物的药代动力学参数如下: The pharmacokinetic parameters of the compounds of the invention are as follows:
Claims
权利要求书： Claims:
1. 通式 (I)所示的化合物或其药学上可以接受的盐、 水合物或溶剂化合物: A compound of the formula (I) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof:
( I ) (I)
Α选自碳原子或氧原子； Α selected from carbon atoms or oxygen atoms;
R选自氢原子或垸基； R is selected from a hydrogen atom or a sulfhydryl group;
R,、 R2、 和 R4各自独立地选自氢原子、 垸基、 烷氧基、 卤素、 芳基或杂芳 基， 其中芳基或杂芳基任选进一步被一个或多个选自烷基、 卤素、 羟基、 四唑基、 咪唑、 二氢咪唑、 羧酸或羧酸酯的取代基所取代； R, R 2 , and R 4 are each independently selected from a hydrogen atom, a fluorenyl group, an alkoxy group, a halogen, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkane Substituted by a substituent of a halogen, a hydroxyl group, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester;
R5、 和 R7各自独立地选自氢原子、 垸基、 烷氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； R 5 and R 7 are each independently selected from a hydrogen atom, a decyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
R8、 R9、 R1G和 Ru各自独立地选自氢原子或垸基； 且 R 8 , R 9 , R 1G and R u are each independently selected from a hydrogen atom or a fluorenyl group;
n是 0， 1或 2。 n is 0, 1 or 2.
2. 根据权利要求 1所述的化合物或其药学上可接受的盐、 水合物或溶剂化合物， 其中： The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein:
A选自碳原子或氧原子； A is selected from a carbon atom or an oxygen atom;
R选自氢原子或垸基； R is selected from a hydrogen atom or a sulfhydryl group;
是芳基或杂芳基，其中芳基或杂芳基任选进一步被一个或多个选自垸基、卤 素、 羟基、 四唑基、 咪唑、 二氢咪唑、 羧酸或羧酸酯的取代基所取代； R2、 和 R4各自独立地选自氢原子、 垸基、 垸氧基或卤素； Is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted by one or more selected from the group consisting of fluorenyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid esters Substituted; R 2 , and R 4 are each independently selected from a hydrogen atom, a fluorenyl group, a decyloxy group or a halogen;
、 和 R7各自独立地选自氢原子、 烷基、 垸氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； And R 7 are each independently selected from a hydrogen atom, an alkyl group, a decyloxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
R8、 R9、 R1Q和 Ru各自独立地选自氢原子或烷基； 且 R 8 , R 9 , R 1Q and Ru are each independently selected from a hydrogen atom or an alkyl group;
n是 0， 1或 2。 根据权利要求 1或 2所述的化合物或其药学上可接受的盐、水合物或溶剂化合
物， 其中所述的化合物选自 n is 0, 1 or 2. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof And wherein the compound is selected from the group consisting of
4. 通式 (IA)所示的化合物， 所述化合物为合成如权利要求 1所述的通式 (I)化合物 的中间体： A compound represented by the formula (IA), which is an intermediate for synthesizing the compound of the formula (I) according to claim 1:
R5、 和 R7各自独立地选自氢原子、 烷基、 烷氧基、 卤素、 羟基、 氨基、 硝 基、 氰基、 羧酸或羧酸酯； R 5 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;
R8、 R9、 RI Q和 Rn各自独立地选自氢原子或垸基； 且 R 8 , R 9 , R IQ and Rn are each independently selected from a hydrogen atom or a fluorenyl group;
n是 0， 1或 2。 n is 0, 1 or 2.
5. 根据权利要求 4所述的化合物， 其中所述的化合物选自: 5. The compound of claim 4, wherein the compound is selected from the group consisting of:
6. 制备根据权利要求 4所述的通式 (IA)化合物的方法， 该方法包括： 6. A method of preparing a compound of formula (IA) according to claim 4, the method comprising:
( I A) ( I A)
将氨基取代的苯并多元环与亚硝酸钠在酸性溶液中进行重氮化反应，再通过氯 化亚锡还原得到肼， 将肼与羰基化合物在溶剂中加热下缩合得到通式 (IA)化合物。 7. 制备根据权利要求 1所述的通式 (I)化合物的方法， 该方法包括： The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, and the hydrazine is condensed with a carbonyl compound in a solvent to obtain a compound of the formula (IA). . 7. A process for the preparation of a compound of formula (I) according to claim 1 which comprises:
( I A) ( I ) ( I A) ( I )
将取代的苯胺类化合物与亚硝酸钠在酸性溶液中进行重氮化反应， 再与通式 Diazotization of a substituted aniline compound with sodium nitrite in an acidic solution, followed by a general formula
(ΙΑ)化合物在碱性溶液中发生偶联反应从而得到通式①化合物。 The (ΙΑ) compound undergoes a coupling reaction in an alkaline solution to give a compound of the formula 1.
8. 根据权利要求 1-5任一项所述的化合物或其盐、水合物或溶剂化合物在制备血
小板生成素 (TPO)受体激动剂中的用途。 The compound according to any one of claims 1 to 5, or a salt, hydrate or solvent compound thereof, for preparing blood Use in small plateogenin (TPO) receptor agonists.
9. 根据权利要求 1-5任一项所述的化合物或其盐、水合物或溶剂化合物在制备治 疗血小板减少症药物中的用途。 The use of a compound according to any one of claims 1 to 5, or a salt, hydrate or solvate thereof, for the manufacture of a medicament for treating thrombocytopenia.
10. 根据权利要求 9 所述的用途， 其中所述药物进一歩与选自下列的药物联合使 用： 集落刺激因子、 细胞因子、 趋化因子、 白细胞介素或细胞因子受体激动剂或 拮抗剂、 可溶的受体、 受体激动剂或拮抗剂抗体或与一个或多个与所述药物具有 相同的作用机理的肽或小分子类物质。 10. The use according to claim 9, wherein the drug is further administered in combination with a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist A soluble receptor, a receptor agonist or an antagonist antibody or a peptide or small molecule substance having one or more of the same mechanism of action as the drug.
1 1. 一种药物组合物， 所述组合物包括有效剂量的如权利要求 1 -5任一项所述的化 合物及其药学上可以接受的盐、 水合物或溶剂化合物， 及药学上可以接受的载体。 1 1. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable a.
12. 根据权利要求 11所述的药物组合物， 其中所述组合物进一步含有联合使用的 治疗有效量的选自下列的药物： 集落刺激因子、 细胞因子、 趋化因子、 白细胞介 素或细胞因子受体激动剂。 The pharmaceutical composition according to claim 11, wherein the composition further comprises a therapeutically effective amount of a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine Receptor agonist.
13. 根据权利要求 11所述的药物组合物在制备治疗血小板减少症药物的用途。
13. Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of thrombocytopenia.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009800001980A CN101679286B (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| UAA201008616A UA101172C2 (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| EP09703490.4A EP2236500B1 (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| ES09703490.4T ES2533366T3 (en) | 2008-01-10 | 2009-01-04 | Azoic derivatives of bicyclo-substituted pyrazolone, preparation procedure and pharmaceutical use thereof |
| CA2711535A CA2711535C (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| MX2010007553A MX2010007553A (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof. |
| US12/812,119 US8367710B2 (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| BRPI0907234-9A BRPI0907234B1 (en) | 2008-01-10 | 2009-01-04 | BICYCLE-REPLACED PIRAZOLON-AZO DERIVATIVES, ITS USE, INTERMEDIATE AND ITS PREPARATION PROCESSES, PHARMACEUTICAL COMPOSITION AND USE |
| AU2009207966A AU2009207966B2 (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| JP2010541680A JP5441269B2 (en) | 2008-01-10 | 2009-01-04 | Bicyclo-substituted pyrazolone-azo derivatives, their preparation process and pharmaceutical use |
| RU2010127786/04A RU2488582C2 (en) | 2008-01-10 | 2009-01-04 | Bicyclosubstituted pyrazolon azo derivatives, method for production and pharmaceutical use thereof |
| HK10102994.0A HK1134818A1 (en) | 2008-01-10 | 2010-03-23 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
| ZA2010/04794A ZA201004794B (en) | 2008-01-10 | 2010-07-07 | Bicyclo-substituted pyrazolon azo derivatives,preparation process and pharmaceutical use thereof |
| US13/742,633 US20130123507A1 (en) | 2008-01-10 | 2013-01-16 | Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof |
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| CN200810000346.6 | 2008-01-10 | ||
| CNA2008100003466A CN101481352A (en) | 2008-01-10 | 2008-01-10 | Bicycle substituted pyrazolone azo derivative, preparation thereof and use in medicine |
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| US (2) | US8367710B2 (en) |
| EP (1) | EP2236500B1 (en) |
| JP (1) | JP5441269B2 (en) |
| KR (1) | KR101556808B1 (en) |
| CN (2) | CN101481352A (en) |
| AU (1) | AU2009207966B2 (en) |
| BR (1) | BRPI0907234B1 (en) |
| CA (1) | CA2711535C (en) |
| ES (1) | ES2533366T3 (en) |
| HK (1) | HK1134818A1 (en) |
| MX (1) | MX2010007553A (en) |
| PT (1) | PT2236500E (en) |
| RU (1) | RU2488582C2 (en) |
| UA (1) | UA101172C2 (en) |
| WO (1) | WO2009092276A1 (en) |
| ZA (1) | ZA201004794B (en) |
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| WO2010142137A1 (en) * | 2009-06-11 | 2010-12-16 | 江苏恒瑞医药股份有限公司 | Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof |
| EP2492262A1 (en) * | 2009-10-23 | 2012-08-29 | Nissan Chemical Industries, Ltd. | Fused heterocyclic compound and thrombopoietin receptor activator |
| CN103724206A (en) * | 2014-01-17 | 2014-04-16 | 青岛农业大学 | Preparation method of 2-bromo-4-fluoro-6-nitrophenol and agriculture activities thereof |
| CN106994120A (en) * | 2016-01-22 | 2017-08-01 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing bicycle substituted pyrazolone azo analog derivative or its salt and preparation method thereof |
| WO2022228551A1 (en) * | 2021-04-30 | 2022-11-03 | 江苏恒瑞医药股份有限公司 | Administration scheme for thrombopoietin receptor agonist |
| WO2023143364A1 (en) * | 2022-01-25 | 2023-08-03 | 江苏恒瑞医药股份有限公司 | Dosage regimen for thrombopoietin receptor agonist |
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| SE0302486D0 (en) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| CN103360317B (en) * | 2012-04-11 | 2016-12-14 | 齐鲁制药有限公司 | Bicycle substituted pyrazolone azo analog derivative, Preparation Method And The Use |
| WO2015111085A2 (en) * | 2014-01-27 | 2015-07-30 | Cadila Healthcare Limited | Processes for the preparation of eltrombopag and pharmaceutically acceptable salts, solvates and intermediates thereof |
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| MX2018008342A (en) * | 2016-01-22 | 2019-01-31 | Jiangsu Hengrui Medicine Co | Pharmaceutical composition comprising bicyclo-substituted pyrazolon azo derivative or salt thereof and preparation method thereof. |
| WO2018133818A1 (en) * | 2017-01-19 | 2018-07-26 | 江苏恒瑞医药股份有限公司 | Method for preparing bicyclo-substituted pyrazolone azo derivatives and intermediates thereof |
| CN110028497B (en) * | 2018-01-11 | 2020-11-17 | 江苏恒瑞医药股份有限公司 | Crystal form of ethanolamine salt of thrombopoietin simulant and preparation method thereof |
| CN113226463A (en) * | 2019-01-08 | 2021-08-06 | 江苏恒瑞医药股份有限公司 | Dosing regimens for bicyclic substituted pyrazolone azo derivatives |
| CN112062699B (en) * | 2020-11-13 | 2021-02-26 | 苏州开元民生科技股份有限公司 | Preparation method of o-aminothiophenol |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040750A1 (en) | 1995-06-07 | 1996-12-19 | Glaxo Group Limited | Peptides and compounds that bind to a thrombopoietin receptor |
| WO1998025965A2 (en) | 1996-12-11 | 1998-06-18 | Glaxo Group Limited | Peptides and compounds that bind to the thrombopoietin receptor |
| WO1999011262A1 (en) | 1997-09-02 | 1999-03-11 | Roche Diagnostics Gmbh | Mpl-receptor ligands, process for their preparation, medicaments containing them and their use for the treatment and prevention of thrombocytopaenia and anaemia |
| WO2000028987A1 (en) | 1998-11-17 | 2000-05-25 | Smithkline Beecham Corporation | Methods of treating thrombocytopenia |
| WO2000035446A1 (en) | 1998-12-17 | 2000-06-22 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| WO2000039773A1 (en) | 1998-12-14 | 2000-07-06 | Mannesmann Ag | Method for transmitting traffic information |
| WO2001007423A1 (en) | 1999-07-26 | 2001-02-01 | Shionogi & Co., Ltd. | Drug compositions exhibiting thrombopoietin agonism |
| WO2001017349A1 (en) | 1999-09-10 | 2001-03-15 | Smithkline Beckman Corporation | Thrombopoietin mimetics |
| WO2001034585A1 (en) | 1999-11-05 | 2001-05-17 | Smithkline Beecham Corporation | Semicarbazone derivatives and their use as thrombopoietin mimetics |
| WO2001053267A1 (en) | 2000-01-24 | 2001-07-26 | Shionogi & Co., Ltd. | Compounds exhibiting thrombopoietin receptor agonism |
| WO2001089457A2 (en) | 2000-05-25 | 2001-11-29 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| WO2005066115A2 (en) | 2003-12-26 | 2005-07-21 | Allergan, Inc. | Disubstituted chalcone oximes having rarϝ retinoid receptor antagonist activity |
| WO2006064957A1 (en) | 2004-12-14 | 2006-06-22 | Nissan Chemical Industries, Ltd. | Amide compound and thrombopoietin receptor activator |
| WO2007044982A2 (en) * | 2005-10-13 | 2007-04-19 | Smithkline Beecham Corporation | Methods for the preservation of platelet efficacy during storage |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB775216A (en) * | 1954-02-23 | 1957-05-22 | Sandoz Ltd | Improvements in or relating to monoazo dyestuffs of the benzene-azo-pyrazolone series and their chromium-complex compounds |
| GB806709A (en) * | 1955-04-22 | 1958-12-31 | Bayer Ag | Monoazo dyestuffs of the benzene-azo-pyrazolone series and metal complexes thereof |
| JPH111477A (en) | 1997-06-12 | 1999-01-06 | Hokuriku Seiyaku Co Ltd | 1,4-benzodiazepine and use thereof |
| EP1244446B1 (en) | 1999-12-06 | 2006-11-02 | SmithKline Beecham Corporation | Thrombopoietin mimetics |
| TWI280128B (en) * | 2002-05-22 | 2007-05-01 | Smithkline Beecham Corp | 3'-[(2Z)-[1-(3,4- dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) |
| EP2387998A1 (en) * | 2003-04-29 | 2011-11-23 | Glaxosmithkline LLC | Methods for treating degenerative diseases/injuries |
| JP4518819B2 (en) * | 2004-03-17 | 2010-08-04 | 富士フイルム株式会社 | Azo compounds |
| BRPI0620532A2 (en) * | 2005-11-23 | 2011-11-16 | Ligand Pharm Inc | compounds and methods for modulating thrombopoietin activity |
-
2008
- 2008-01-10 CN CNA2008100003466A patent/CN101481352A/en active Pending
-
2009
- 2009-01-04 WO PCT/CN2009/000001 patent/WO2009092276A1/en active Application Filing
- 2009-01-04 UA UAA201008616A patent/UA101172C2/en unknown
- 2009-01-04 US US12/812,119 patent/US8367710B2/en active Active
- 2009-01-04 EP EP09703490.4A patent/EP2236500B1/en active Active
- 2009-01-04 RU RU2010127786/04A patent/RU2488582C2/en active
- 2009-01-04 BR BRPI0907234-9A patent/BRPI0907234B1/en active IP Right Grant
- 2009-01-04 AU AU2009207966A patent/AU2009207966B2/en active Active
- 2009-01-04 JP JP2010541680A patent/JP5441269B2/en active Active
- 2009-01-04 ES ES09703490.4T patent/ES2533366T3/en active Active
- 2009-01-04 PT PT97034904T patent/PT2236500E/en unknown
- 2009-01-04 MX MX2010007553A patent/MX2010007553A/en active IP Right Grant
- 2009-01-04 CN CN2009800001980A patent/CN101679286B/en active Active
- 2009-01-04 KR KR1020107017630A patent/KR101556808B1/en active IP Right Grant
- 2009-01-04 CA CA2711535A patent/CA2711535C/en active Active
-
2010
- 2010-03-23 HK HK10102994.0A patent/HK1134818A1/en unknown
- 2010-07-07 ZA ZA2010/04794A patent/ZA201004794B/en unknown
-
2013
- 2013-01-16 US US13/742,633 patent/US20130123507A1/en not_active Abandoned
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040750A1 (en) | 1995-06-07 | 1996-12-19 | Glaxo Group Limited | Peptides and compounds that bind to a thrombopoietin receptor |
| WO1998025965A2 (en) | 1996-12-11 | 1998-06-18 | Glaxo Group Limited | Peptides and compounds that bind to the thrombopoietin receptor |
| WO1999011262A1 (en) | 1997-09-02 | 1999-03-11 | Roche Diagnostics Gmbh | Mpl-receptor ligands, process for their preparation, medicaments containing them and their use for the treatment and prevention of thrombocytopaenia and anaemia |
| WO2000028987A1 (en) | 1998-11-17 | 2000-05-25 | Smithkline Beecham Corporation | Methods of treating thrombocytopenia |
| WO2000039773A1 (en) | 1998-12-14 | 2000-07-06 | Mannesmann Ag | Method for transmitting traffic information |
| WO2000035446A1 (en) | 1998-12-17 | 2000-06-22 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| WO2001007423A1 (en) | 1999-07-26 | 2001-02-01 | Shionogi & Co., Ltd. | Drug compositions exhibiting thrombopoietin agonism |
| WO2001017349A1 (en) | 1999-09-10 | 2001-03-15 | Smithkline Beckman Corporation | Thrombopoietin mimetics |
| WO2001034585A1 (en) | 1999-11-05 | 2001-05-17 | Smithkline Beecham Corporation | Semicarbazone derivatives and their use as thrombopoietin mimetics |
| WO2001053267A1 (en) | 2000-01-24 | 2001-07-26 | Shionogi & Co., Ltd. | Compounds exhibiting thrombopoietin receptor agonism |
| WO2001089457A2 (en) | 2000-05-25 | 2001-11-29 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| WO2005066115A2 (en) | 2003-12-26 | 2005-07-21 | Allergan, Inc. | Disubstituted chalcone oximes having rarϝ retinoid receptor antagonist activity |
| WO2006064957A1 (en) | 2004-12-14 | 2006-06-22 | Nissan Chemical Industries, Ltd. | Amide compound and thrombopoietin receptor activator |
| WO2007044982A2 (en) * | 2005-10-13 | 2007-04-19 | Smithkline Beecham Corporation | Methods for the preservation of platelet efficacy during storage |
Non-Patent Citations (10)
| Title |
|---|
| BARLEY ET AL., CELL, vol. 77, 1994, pages 1117 - 1124 |
| KAUSHANSKY ET AL., NATURE, vol. 369, 1994, pages 568 - 571 |
| KUTER D.I. ET AL., THE ONCOLOGIST, vol. 1, 1996, pages 98 - 106 |
| KUTER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 91, 1994, pages 11104 - 11108 |
| METCALF, NATURE, vol. 369, 1994, pages 519 - 520 |
| SAUVAGE ET AL., NATURE, vol. 369, 1994, pages 533 - 538 |
| See also references of EP2236500A4 |
| VIGON ET AL., PROC. NAT. ACAD. SCI., vol. 89, 1992, pages 5640 - 5644 |
| WENDLING ET AL., NATURE, vol. 369, 1994, pages 571 - 574 |
| WENDLING, F., BIOTHERAPY, vol. 10, no. 4, 1998, pages 269 - 77 |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010142137A1 (en) * | 2009-06-11 | 2010-12-16 | 江苏恒瑞医药股份有限公司 | Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof |
| US8642637B2 (en) | 2009-06-11 | 2014-02-04 | Jiangsu Hengrui Medicine Co., Ltd. | Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof |
| US9120762B2 (en) | 2009-06-11 | 2015-09-01 | Jiangsu Hengrui Medicine Co., Ltd. | Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof |
| EP2492262A1 (en) * | 2009-10-23 | 2012-08-29 | Nissan Chemical Industries, Ltd. | Fused heterocyclic compound and thrombopoietin receptor activator |
| EP2492262A4 (en) * | 2009-10-23 | 2013-03-20 | Nissan Chemical Ind Ltd | Fused heterocyclic compound and thrombopoietin receptor activator |
| US8889732B2 (en) | 2009-10-23 | 2014-11-18 | Nissan Chemical Industries, Ltd. | Fused heterocyclic compounds and thrombopoietin receptor activators |
| JP5704073B2 (en) * | 2009-10-23 | 2015-04-22 | 日産化学工業株式会社 | Fused ring heterocyclic compounds and thrombopoietin receptor activators |
| CN103724206A (en) * | 2014-01-17 | 2014-04-16 | 青岛农业大学 | Preparation method of 2-bromo-4-fluoro-6-nitrophenol and agriculture activities thereof |
| CN106994120A (en) * | 2016-01-22 | 2017-08-01 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing bicycle substituted pyrazolone azo analog derivative or its salt and preparation method thereof |
| CN106994120B (en) * | 2016-01-22 | 2021-05-14 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing bicyclo-substituted pyrazolone azo derivative or salt thereof and preparation method thereof |
| WO2022228551A1 (en) * | 2021-04-30 | 2022-11-03 | 江苏恒瑞医药股份有限公司 | Administration scheme for thrombopoietin receptor agonist |
| WO2023143364A1 (en) * | 2022-01-25 | 2023-08-03 | 江苏恒瑞医药股份有限公司 | Dosage regimen for thrombopoietin receptor agonist |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2711535A1 (en) | 2009-07-30 |
| HK1134818A1 (en) | 2010-05-14 |
| AU2009207966A1 (en) | 2009-07-30 |
| UA101172C2 (en) | 2013-03-11 |
| EP2236500B1 (en) | 2014-12-24 |
| CN101679286B (en) | 2011-06-08 |
| MX2010007553A (en) | 2010-10-04 |
| BRPI0907234A2 (en) | 2020-08-04 |
| JP2011509263A (en) | 2011-03-24 |
| US8367710B2 (en) | 2013-02-05 |
| EP2236500A4 (en) | 2012-08-22 |
| JP5441269B2 (en) | 2014-03-12 |
| CN101481352A (en) | 2009-07-15 |
| US20130123507A1 (en) | 2013-05-16 |
| CA2711535C (en) | 2015-12-15 |
| BRPI0907234B1 (en) | 2021-08-10 |
| AU2009207966B2 (en) | 2013-03-21 |
| CN101679286A (en) | 2010-03-24 |
| PT2236500E (en) | 2015-04-07 |
| RU2010127786A (en) | 2012-02-20 |
| ES2533366T3 (en) | 2015-04-09 |
| KR20100120141A (en) | 2010-11-12 |
| US20100316601A1 (en) | 2010-12-16 |
| KR101556808B1 (en) | 2015-10-01 |
| RU2488582C2 (en) | 2013-07-27 |
| ZA201004794B (en) | 2011-09-28 |
| EP2236500A1 (en) | 2010-10-06 |
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